bluuebunny/crossref_metadata_2025 huggingface dataset:
10311- ACT-19 A GLOBAL, RANDOMIZED, DOUBLE-BLINDED, PHASE 3 STUDY OF VORASIDENIB VERSUS PLACEBO IN PATIENTS WITH ADULT-TYPE DIFFUSE GLIOMA WITH AN IDH1/2 MUTATION (INDIGO): UPDATED EFFICACY RESULTS
Authors: Van Den Bent Martin J , Mellinghoff Ingo K , Touat Mehdi , Blumenthal Deborah T , Peters Katherine B , Ellingson Benjamin M , Mendez Joe , Yust-Katz Shlomit , Mason Warren P , Hottinger Andreas F , Arakawa Yoshiki , Sepulveda Juan M , Wick Wolfgang , Tron Adriana E , Zhao Dan , Pandya Shuchi S , Steelman Lori , Hassan Islam , Wen Patrick Y , Cloughesy Timothy F
Published: November 2024

INTRODUCTION

The Phase 3 INDIGO study (NCT04164901) evaluated vorasidenib, an oral,brain-penetrant, dual inhibitor of mutated isocitrate dehydrogenase 1/2 (mIDH1/2), in patients with mIDH1/2 diffuse glioma. The primary endpoint of progression-free survival (PFS) per blinded independent review committee (BIRC), and key secondary endpoint of time to next intervention (TTNI), were met in the positive, preplanned second interim analysis (IA2). The study was unblinded in March 2023 following independent data monitoring committee recommendation. Herein, we present results after an additional 6 months of follow-up between the database lock for IA2 (September 6, 2022) and study unblinding (March 7, 2023).

METHODS

Patients with residual/recurrent grade 2 mIDH1/2 oligodendroglioma or astrocytoma were enrolled (aged ≥12 years; Karnofsky Performance Status, ≥80; measurable non-enhancing disease; surgery as only prior treatment; no immediate need of chemoradiotherapy). Patients were randomized 1:1 to vorasidenib 40 mg or placebo daily in 28-day cycles.

RESULTS

Overall, 331 patients were randomized (median age, 40.0 years; oligodendroglioma, 172; astrocytoma, 159). As of March 7, 2023, 123/168 (73%) patients remained on vorasidenib and 72/163 (44%) remained on placebo. PFS per BIRC remained in favor of vorasidenib (HR, 0.35; 95% CI, 0.25–0.49) and was consistent with PFS per investigator assessment (HR, 0.34; 95% CI, 0.23–0.50). Median PFS per BIRC: vorasidenib, not estimable (NE; 95% CI, 22.1–NE); placebo, 11.4 months (95% CI, 11.1–13.9). TTNI also remained in favor of vorasidenib (HR, 0.25; 95% CI, 0.16–0.40). Median TTNI: vorasidenib, NE (95% CI, NE–NE); placebo, 20.1 months (95% CI, 17.5–27.1). No new safety signals emerged.

CONCLUSIONS

Vorasidenib is a targeted therapy for patients with predominantly non-enhancing mIDH1/2 diffuse glioma following surgical intervention, as shown in the INDIGO population. These additional 6 months of follow-up confirm the previously reported statistically significant and clinically meaningful improvements in PFS and TTNI with vorasidenib.
10189- STMO-12 INTRAOPERATIVE NEUROMONITORING FOR THE LOWER-EXTREMITY REGION USING MOTOR-EVOKED POTENTIAL WITH DIRECT CORTICAL STIMULATION IN BRAIN TUMOR SURGERIES
Authors: Matsujda Ryosuke , Takatani Tsunenori , Hayashi Hironobu , Maeoka Ryosuke , Morisaki Yudai , Yokoyama Shohei , Takeshima Yasuhiro , Kawaguchi Masahiko , Nakagawa Ichiro
Published: November 2024

PURPOSE

To evaluate the motor function of the lower extremity (LE), we used direct cortical stimulation motor-evoked potential (D-MEP) monitoring with a single six-contact subdural strip electrode placed in the interhemispheric fissure.

METHODS

Intraoperative neuromonitoring using D-MEPs in the LE was performed in 18 cases (16 patients) for brain tumor surgery with a follow-up period of at least 3 months from December 2018 to April 2023. After dural opening, a single six-contact subdural strip electrode was placed inside the interhemispheric fissure. To identify the central sulcus, phase reversal was recorded using SSEPs. Next, direct cortical stimulation was applied to the PMC. The baseline waveform was defined as a reproducible waveform of 30 μV or higher, and a significant decrease of >50% in the amplitude resulted in a warning during surgery.

RESULTS

The success rate of central sulcus identification in the LE was 66.7% (12/18 cases). D-MEP monitoring could record stable contralateral MEPs of the tibialis anterior, gastrocnemius, and abductor hallucis in 16 of 18 cases (88.9%). The mean intensity of stimulation for D-MEPs was 20.5 ± 9.9 mA, and the 16 cases showed no significant reduction in amplitude. Seventeen cases showed no deterioration of motor function of the LE at 1 and 3 months postoperatively. In the remaining case with unsuccessful D-MEP, paralysis of the LE worsened at 1 and 3months postoperatively.

CONCLUSION

The placement of electrodes in the interhemispheric fissure on the PMC of the LE enabled motor-function monitoring in the LE with D-MEPs, suggesting that D-MEP-based monitoring may be a reliable approach.
10261- STMO-22 RADICAL SURGICAL RESECTION FOR THALAMIC TUMORS USING OCCIPITAL TRANSTENTORIAL APPROACH WITH INTRAOPERATIVE MRI
Authors: Hanihara Mitsuto , Kazama Hirofumi , Saito Ryu , Yoshioka Hideyuki , Kinouchi Hiroyuki
Published: November 2024

BACKGROUND

Thalamic tumor has been one of the most challenging part to operate in neurosurgery due to its risks associated with surgical procedures. Occipital transtentorial approach (OTA) is adaptable not only pineal lesion but also thalamic tumor located at pulvinar part. Intraoperative MRI (iMRI) has proven to be highly useful in these procedures, providing real-time imaging that enhances the precision of tumor resection and minimizes the risk of damage to surrounding critical structures.

OBJECTIVE

To examine our surgical outcome and usefulness of OTA for thalamic gliomas. We present a retrospective review of our surgical experience with 4 patients presenting symptomatic thalamic gliomas.

METHODS

OTA was used by prone position with an ipsilateral entry. Following tent incision and dissecting arachnoid membranes around deep vein complex, resection of tumor was performed with making cleavage between tumor and normal brain. Neuronavigation and transcranial motor evoked potentials and intraoperative magnetic resonance imaging (iMRI) were used in all cases.

RESULTS

Four patients with intrinsic gliomas located at the thalamus and midbrain were operated on. One case with midbrain infiltration resulted in subtotal resection, while total resection was achieved in the remaining three cases. Pathological diagnoses are diffuse astrocytoma, pilocytic astrocytoma, pilomyxoid astrocytoma, and anaplastic pilocytic astrocytoma. Postoperative radiochemotherapy was added in one case of anaplastic pilocytic astrocytoma, respectively. The average follow-up period was 54.9 months, during which all cases maintained independent ADL without tumor recurrence.

CONCLUSION

OTA for thalamic gliomas who has main mass located at pulvinar part is a safe and reliable approach with the application of high resolution iMRI.
10002- MPC-1 HISTOLOGICAL GRADE AND TP53 MUTATIONS STRATIFY PROGNOSIS IN MOLECULAR GLIOBLASTOMA
Authors: Makino Ryutaro , Higa Nayuta , Akahane Toshiaki , Yonezawa Hajime , Uchida Hiroyuki , Takajo Tomoko , Kirishima Mari , Yokoyama Seiya , Otsuji Ryosuke , Fujioka Yutaka , Kuga Daisuke , Yamahata Hitoshi , Horie Nobutaka , Kurosaki Masamichi , Yamamoto Junkoh , Yoshimoto Koji , Tanimoto Akihide , Hanaya Ryosuke
Published: November 2024

BACKGROUND

In the 2021 WHO Central Nervous System tumor classification, the Glioblastoma, IDH-wildtype diagnosis has changed markedly. We compared the clinical backgrounds and prognoses of molecular glioblastoma (mGBM) and conventional glioblastoma (histological glioblastoma, hGBM) in a Japanese cohort.

METHODS

We included 274 patients with glioblastoma who were treated at five institutions from 2011 to 2023. Driver gene analysis was performed using a brain tumor-specific custom gene panel to verify the association between molecular and clinical information.

RESULTS

Patients with mGBM had a better preoperative KPS, lower Ki-67, and lower removal rates than did those who had hGBM. Overall survival was longer in patients with mGBM than in those with hGBM (1207 vs 598 days, p = 0.032). TP53 mutation (hazard ratio: 5.33, 95% confidence interval: 0.26 - 108.7, p = 0.012) and histological grade 3 (p = 0.045) were significant poor prognostic factors in mGBM.

CONCLUSION

Patients with mGBM had better preoperative KPS, worse removal rates, lower Ki-67 labeling index, and better overall survival than did those with hGBM. Additionally, histological grade of mGBM is potentially useful for estimating prognosis. Glioblastoma in the WHO CNS5 2021 remains a heterogeneous population, and prognostic stratification based on the patient’s clinical background and molecular information is desirable.
10182- NI-15 ANALYSIS OF THE HIGH UPTAKE PATTERN ON 11C-METHIONINE-PET IN ADULT NON-ENHANCED GLIOMAS
Authors: Yasuda Shoji , Imai Naoya , Ikegame Yuka , Ikuta Soko , Maruyama Takashi , Kumagai Morio , Muragaki Yoshihiro , Shinoda Jun , Yano Hirohito
Published: November 2024

The uptake pattern of adult non-enhanced gliomas on 11C-methionine (MET) positron emission tomography (PET) was detected in each type of tumor. This study included 52 cases of astrocytoma (A group), 34 cases of oligodendroglioma (O group), and 21 cases of glioblastoma (G group). Region of interest (ROI) was defined based on T2-weighted imaging high intensity lesions, encompassing each tumor volume. Maximum or mean standardized uptake value (SUV) and tumor/normal frontal cortex SUV ratio (TNR) were calculated from PET data. ROIs were layered internally by 5mm intervals from the tumor edge to assess the MET distribution. A high uptake pattern, meaning a TNR of 2.0 or higher, was classified by three observers. TNR, maximum, and mean SUV of the tumor were significantly lower in the A group than in the O and G groups. Although total tumor volume did not differ among groups, there were very strong correlations between increasing TNR and volume with TNR of 1.3 or higher and 2.0 or higher in the A and the O group (r=0.73-0.93); relatively poor relation in the G group (r=0.53-0.70). Maximum SUV was predominantly observed at the outermost layers across all groups, with the O group frequently exhibiting it at the layers of 5-10mm from the tumor edge (40.6%). Among 28 cases with a TNR of 2.0 or higher, the extent of high uptake area was classified into whole patterns in 5 cases and partial or spot patterns in 23 cases. The high MET distributions of the cases with partial or spot patterns were all identified as central or surface/outside patterns, and there were no cases with surface/inside pattern. The characteristic uptake patterns for each tumor subtype may help plan the surgical strategy for gliomas.
IL-4 IMMUNOTHERAPY TARGETING THE UNIQUE EXTRACELLULAR MATRIX IN RECURRENT GLIOBLASTOMA
Authors: Osuka Satoru
Published: November 2024

Glioblastoma (GBM) is an aggressive primary brain tumor characterized by high treatment resistance and an extremely high rate of recurrence. To understand the mechanisms of treatment resistance and develop novel therapeutic approaches, we prepared 11 patient-derived human GBM cells and 5 mouse GBM cells from genetically engineered mouse models. We performed repeated irradiation for them to analyze the mechanisms of acquired resistance. During repeated irradiation, GBM cells enhanced radio- and chemo-resistance, increased invasiveness, and elevated ability to establish an immunosuppressive microenvironment. We identified upregulation of Collagen type I and III (COL I & III) as crucial for this adaptive resistance. COL I & III, rarely expressed in normal brain tissue but highly expressed in resistant GBM, emerged as potential markers for targeting therapy-resistant GBM tumors. To apply these findings to treatment, we focused on von Willebrand factor (vWF), which selectively binds to expose COL I & III in abnormal tissues. We developed CBD-IL-12 by conjugating vWF’s collagen-binding domain (CBD) into the immunostimulatory cytokine IL-12. In mouse models of therapy-resistant GBM, intravenously administered CBD-IL-12 accumulated specifically in tumor sites, without accumulating in normal brain tissue or other healthy organs. CBD-IL-12 enhanced dendritic cell recruitment, increased CD8+ T cell infiltration, and improved the immunosuppressive tumor environment, resulting in tumor suppression and significantly prolonged survival. Our findings suggest that extracellular matrix proteins have tumor-specific and abundant presence in the tumor microenvironment, indicating their potential application in targeted therapy. We demonstrated that therapy-resistant GBM cells exhibited upregulated expression of COL I & III, and CBD can be utilized to selectively deliver cytokines to tumor sites. This CBD-based immunotherapy approach shows promise in transforming the treatment landscape for recurrent GBM, offering a novel strategy to combat this challenging malignancy.
Lithospheric strike-slip faulting in central Tibet since 35–32 Ma and implications for the incipient Asian extrusional tectonics
Authors: Lu Haijian , Li Haibing , Xiang Zhongjin , Malusà Marco G , Li Chunrui , Zhang Zhiyong , Wu Lin , Ma Xuxuan , Pan Jiawei
Published: November 2024

The onset age and depth of the central Tibet strike-slip faults are two still unresolved fundamental issues with regard to the Cenozoic tectonic evolution of central Tibet. Here we present a comprehensive dataset of geochronological, geochemical and structural data on recently discovered en-echelon dykes representing the incipient development of strike-slip faulting from the Lunpola basin in central Tibet. Our results provide evidence for mantle-derived, bimodal magmatism linked to lithospheric-scale strike-slip faulting at 35–32 Ma, and demonstrate that the central Tibet strike-slip faults are at least 20 Ma older than previously estimated (15–8 Ma). We suggest that these faults were originally connected with the lithospheric-scale Jiali and Ailao Shan-Red River shear zones exposed farther east, forming part of a straight, 2500–3000 km-long lithospheric shear zone that favored mantle upwelling and magmatic intrusion coeval with substantial uplift (1.5–2 km) of the central Tibet valley in the early Oligocene.
National Study Examining Excellence and Value in Physical Therapist Residency Education: Part 1—Design, Methods, and Results
Authors: Briggs Matthew S , Osborne Raine , Hartley Gregory W , Kraft Sara , Bailey Chloe E , Tichenor Carol Jo , Rapport Mary Jane , Black Lisa , Jensen Gail
Published: November 2024

Objective

A challenge in health professions is training practitioners to navigate health care complexities, promote health, optimize outcomes, and advance their field. Physical therapist residency education offers a pathway to meet these needs in ways that “entry-level” (professional) education may not. Identifying key aspects of excellence in residency education and understanding its value in developing adaptive expertise will help devise strategies to enhance program, resident, and patient outcomes. The objective of this study was to examine current physical therapist residency education practices to identify and describe examples of excellence and value.

Methods

A multi-site, multi-specialty qualitative case series was conducted, examining exemplary physical therapist residency programs and their contextual environments using a social constructivist theoretical lens. Six residency programs operating 20 individual residencies that were considered exemplar were selected for the study to participate in site visits. Qualitative case studies were generated from individual interviews, focus groups, review of artifacts, and field observations. The residencies were diverse in specialty area of practice, setting, and geographic location.

Results

A conceptual framework was generated grounded in the domains of excellence and value. These domains were connected by 3 signature indicators: (1) atmosphere of practice-based learning, (2) embodiment of professional formation, and (3) elevated practice. These signature indicators represent the aggregate effects of the interchange between the excellence and value domains which sustain residency education.

Conclusion

This study builds upon the work of the Physical Therapist Education for the 21st Century (PTE-21) study and identifies key elements of excellence in residency education, the value of such education, and related outcomes. Findings from this study substantiate the need for a postprofessional phase of physical therapist education founded in practice-based learning encapsulated in residency education.

Impact

Results from this study could have compelling and powerful implications on the dialogue and strategic direction in physical therapist residency education.
Silent St. Louis encephalitis virus circulation evidence by a haemovigilance survey in a centralized blood bank
Authors: Blanco Sebastián , Frutos María C , Spinsanti Lorena , Gallego Sandra V
Published: November 2024

Background

Saint Louis encephalitis virus (SLEV) re-emergence and its geographical expansion, evidenced by its emergence in previously unaffected areas, have raised significant public health concerns. We aimed to show the usefulness of haemovigilance as an effective tool to fill arboviruses surveillance gaps to track trends and identify hotspots.

Methods

Within the framework of a blood bank haemovigilance program, we performed a survey to evaluate the potential threat of circulating mosquito-borne infections for transfusion safety. SLEV was detected by a PCR targeting the conserved NS5-gene region, and the PCR-product was subjected to direct nucleotide sequencing reaction.

Results

The SLEV-strain detected in the blood donor (OR236721) clustered with previously reported CbaAr-4005, 79 V-2533, and MN413675 isolated in Córdoba (2005, epidemic), Santa Fe (1979, non-epidemic) and Buenos Aires (2013, non-epidemic), with 97% identity.

Conclusions

Herein, we show the usefulness of haemovigilance in uncovering the silent circulation of arboviral infections. Implementing this systematic surveillance approach would allow for monitoring the distribution and incidence of vector-borne diseases, providing information that could prevent the spread of the virus and its introduction into novel biomes. Ultimately, leveraging haemovigilance enables timely identification of potential outbreaks and empowers policymakers to make well-informed decisions to safeguard public health.
Public/Private Religion in Context: When Psychologists Use Religion to Invigorate Therapy
Authors: Tal Orly , Pagis Michal
Published: November 2024

Previous studies have tracked how the penetration of psychological discourses into the religious sphere turns religion into a private, individual matter. These studies, however, overlook a process that is moving in the opposite direction—the influence of religion on psychology. Based on ethnographic research among licensed psychotherapists who integrate Buddhist or Jewish traditions into their clinical practice, we demonstrate that processes of privatization and de-privatization can take place simultaneously depending on context. In the setting of institutional training and professional gatherings, religion is visible and is used to produce a public, social, and moral vision for an invigorated psychology. By contrast, in the dyadic setting between psychotherapist and patient, religion is kept covert, and while it is significant to the psychotherapist in his/her practice, it remains invisible to the patient. Yet, despite its covert role in the clinical setting, psychotherapists see religion as having a broader ripple impact. We offer the notions of overt and covert sacralization to characterize how religion influences the field of psychology and discuss the implications of this study for the public/private debate.
Phase 2, Multicenter, Open-label, Nonrandomized Study of Neoadjuvant Chemotherapy Liposomal Irinotecan With 5-Fluorouracil, Leucovorin, and Oxaliplatin, Followed by Chemoradiotherapy in Patients With Rectal Cancer in a Watch-and-Wait Program
Authors: Muñoz César , Riesco Martinez María-C. , Ugidos Lisardo , García-Alfonso Pilar , Alvarez-Gallego Rafael , Peinado Paloma , Toledano Carmen , Mihic-Góngora Luka , Ortega Anselmi Justo Gabriel , Sanz Garcia Enrique , Vicente Emilio , Quijano Yolanda , Durán Hipólito J. , Díaz Eduardo , Ferri Valentina , Rubio Carmen , HernandoRequejo Ovidio , López González Mercedes , Prados Susana , López Ulpiano , Allona María , PérezDueñas Virginia , Perez-Escutia María Angeles , Cubillo Antonio
Published: November 2024

Objective:

To evaluate the efficacy of neoadjuvant chemotherapy combination with liposomal irinotecan, 5-fluorouracil, leucovorin, and oxaliplatin in patients with locally advanced rectal cancer.

Methods:

This was a phase 2, nonrandomized, multicenter study in adults with stage II or III rectal cancer and an Eastern Cooperative Oncology Group performance status of 0 to 1. Total neoadjuvant therapy (TNT) consisted of neoadjuvant chemotherapy combination with liposomal irinotecan (60 mg/m2), oxaliplatin (60 mg/m2), leucovorin (400 mg/m2), and fluorouracil (2400 mg/m²), followed by chemoradiotherapy [ie, capecitabine (825 mg/m2) and radiotherapy according to the standard of care]. The primary efficacy endpoint was the proportion of patients who achieved clinical complete response (cCR), defined as the normalization of pelvic magnetic resonance imaging, rectoscopy, computed tomography scan, and tumor markers.

Results:

The median follow-up was 32.3 months. Of the 30 patients who underwent TNT and were evaluated, 6 (20.0%; 95% CI: 5.2%-34.8%) patients achieved a cCR. There were no deaths. The median disease-free survival (DFS) for patients with cCR was not reached after a follow-up of 32 months; the 1-year DFS rate was 90.0% (95% CI: 71.0%-100%), and the 2-year and 3-year DFS rates were 80.0% (95% CI: 55.0%-100%). No grade ≥4 adverse events (AEs) were observed. Grade 3 AEs occurred in 18 patients (60%), most frequent was diarrhea (n = 9, 30%). Eleven (36.7%) patients experienced serious AEs, with diarrhea being the most frequent (n = 6, 20.0%).

Conclusion:

TNT with 5-fluorouracil, leucovorin, and oxaliplatin and chemoradiation is a safe and effective therapeutic alternative for the management of locally advanced rectal cancer.
Exploring the link between SIRT1 gene variants and depression comorbidity in type 2 diabetes
Authors: He Yingxia , Wu Qinqin , Yin Ziwei , Zeng Yi , Xia Ningyu , Zhu Hong
Published: November 2024

This study aims to (1) analyze the clinical characteristics and risk factors of patients with type 2 diabetes and comorbid depression and (2) explore the association between SIRT1 gene single-nucleotide polymorphism sites and this comorbidity. A total of 450 type 2 diabetes patients hospitalized in the General Medicine Department at The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology from July 2022 to September 2023, and 300 healthy individuals from the physical examination department were selected as study subjects. Both groups were assessed using general information surveys and questionnaires. Statistical analyses were performed to compare clinical indicators across 3 groups: individuals with only type 2 diabetes, those with comorbid depression, and healthy controls. The age, gender, disease duration, marital status, income and drug expenditure, employment status, fasting blood glucose level, fasting insulin level difference, insulin resistance index difference, glycated hemoglobin, high-density lipoprotein level, and HCY difference among the 3 groups of patients were risk factors for type 2 diabetes comorbid depression patients. The SIRT1 mRNA level was significantly reduced in type 2 diabetes comorbid depression patients. The SIRT1 gene had 3 sites: rs12415800, rs3758391, and rs932658, which were related to the patient’s type 2 diabetes comorbid depression. They were the additive model and dominant model of rs12415800 and rs3758391, respectively. In addition, the GTGGT haplotype composed of rs12415800–rs932658–rs7895833–rs2273773–rs1467568 and the AGACT haplotype composed of rs3758391–rs932658–rs33957861–rs3818292–rs1467568 were significantly associated with type 2 diabetes comorbid depression. Numerous factors influence the presence of depression in patients with type 2 diabetes, with the SIRT1 gene playing a significant role, serving as a potential biomarker for this comorbidity.
Causal associations between mobile phone usage and glaucoma risk: A Mendelian randomization study
Authors: Song Rui , Wang Yinnuo , Kong Yanbo , Fan Xinyu , Yuan Chuang , Zha Xu
Published: November 2024

Previous research has indicated a possible link between mobile phone usage and the incidence of glaucoma. This study employs a 2-sample Mendelian randomization (MR) analysis to examine the causal relationship between mobile phone use and glaucoma risk. We used single nucleotide polymorphisms (SNPs) from publicly accessible genome-wide association study (GWAS) datasets as instrumental variables (IVs). The primary analytical method was the inverse variance weighted (IVW) approach, with MR-Egger and weighted median analyses serving as complementary methods. Sensitivity was evaluated using Cochran’s Q test and MR-Egger regression. The results demonstrate a causal effect of mobile phone usage on an increased risk of glaucoma (ORIVW = 1.358, 95% CI: 1.052–1.752, P = .019; ORMR-Egger = 1.882, 95% CI: 0.53–6.682, P = .337; ORWeighted median = 1.387, 95% CI: 1.012–1.900, P = .042; ORMR-PRESSO = 1.358, 95% CI: 1.052–1.752, P = .026). Sensitivity analyses confirmed the robustness and reliability of these findings. The study identifies mobile phone usage as a potentially modifiable risk factor for glaucoma, providing new avenues for exploring the specific mechanisms underlying these ocular disorders.
Clinical management of hypophosphatemic osteomalacia induced by adefovir and tenofovir: Insights from a case report
Authors: He Yinhui , Huang Xin , Ye Yongjun , Xu Haiyan
Published: November 2024

Rationale:

Hypophosphatemic osteomalacia is a rare chronic metabolic bone disease characterized by low serum phosphate levels owing to genetic or acquired causes. This article presents a case report of the clinical management, challenges encountered, and prognosis of secondary hypophosphatemic osteomalacia induced by defovir and tenofovir.

Patient concerns:

A 55-year-old male patient had been experiencing persistent dull chest pain and fatigue for more than a year. The patient had chronic hepatitis B infection for over 10 years, with regular use of adefovir dipivoxil capsules for more than 10 years. Five months before admission, the patient was switched to tenofovir alafenamide fumarate tablets.

Diagnoses:

After obtaining clinical manifestations, medical history, and examination results, tumor-induced osteomalacia was excluded, and the final diagnosis was drug-induced hypophosphatemic osteomalacia.

Interventions:

Adefovir dipivoxil and tenofovir alafenamide were discontinued, and the patient was switched to entecavir disintegration tablets for antiviral therapy. He was advised to follow a high-phosphate diet, receive phosphorus supplementation and calcitriol capsules to promote calcium absorption, obtain moderate sun exposure, and take measures to prevent falls and fractures.

Outcomes:

Serum phosphate levels showed a gradual upward trend, with the most recent measurement being 0.85 mmol/L. The bone density gradually improved and reached normal levels in the most recent assessment. The symptoms of fatigue and chest pain were resolved.

Lessons:

Accurate diagnosis requires a combination of clinical presentation, medical history, biochemical and radiological findings, and, if available, measurement of fibroblast growth factor 23 (FGF 23). The role of national, provincial, or regional centers for rare diseases is crucial for conducting unconventional tests and providing access to rare medications.
Methods for detecting and monitoring Salmonella infection and chronic carriage in living mice using bioluminescent in vivo imaging
Authors: Bennett Aliyah N. , Laipply Baileigh , Gunn John S.
Published: November 2024

Salmonella enterica serovar Typhi primarily persists in chronic carriers by forming biofilms on gallstones in the gallbladder. We have developed a gallstone mouse model to study chronic carriage. To better understand the infection timeline and differentiate between mice that have maintained long-term gallbladder carriage from those that have cleared infection, we utilized bioluminescent S. Typhimurium and in vivo imaging to detect and track the organ-specific presence of bacteria in living mice. The mice infected with our bioluminescent S. Typhimurium showed luminescence in the abdomen as early as 3 days in comparison to the mice infected with non-luminescent WT S. Typhimurium. With our methods, we achieve image resolution such that we can confidently identify the presence of S. Typhimurium in the gallbladder at >60 days post-infection. Using these methods, we have determined that the minimum number of bacteria necessary to detect luminescence in the mice is 103 c.f.u. and that one out of six initially infected mice will remain persistently infected for greater than 60 days, with gallbladder bacterial loads reaching upwards of 103 per milligram of tissue. Given that our limit of detection of luminescence is 103 c.f.u., our sensitivity is robust enough to identify the bacterial loads present in the average chronically infected mouse. The quantification of individual organs’ bacterial c.f.u. and comparison of luminescence between WT and luminescent S. Typhimurium validate that our technique is specific and sensitive enough to detect organ-specific infection in our model of typhoidal chronic carriage.
Tossing the coin of ESBL: 50% prevalence of ESBL-producing Klebsiella pneumoniae isolated from bloodstream infections of patients with features of sepsis at a national referral and teaching hospital of a low-income setting.
Authors: Achan Beatrice , Luggya Tonny , Kajumbula Henry
Published: November 2024

Background.

Klebsiella pneumoniae is part of the ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp) group of MDR pathogens. It is the second leading cause of nosocomial bloodstream infections, and it has a propensity to be drug resistant. Therefore, it was aimed to determine the antibiotic resistance patterns of K. pneumoniae isolated from blood cultures of patients with features of sepsis at Mulago National Referral Hospital, Uganda.
Methods
The cross-sectional study on patients with features of sepsis utilised K. pneumoniae (N= 30) isolated from positive blood culture specimens. The antibiotic resistance profile was determined by the Clinical and Laboratory Standards Institute’s Kirby Bauer disk diffusion method, which was used to classify the isolates as susceptible, intermediate, and resistant. K. pneumoniae isolates that were resistant to third generation cephalosporins were subjected to extended spectrum b-lactamase (ESBL) screening and confirmation using the double-disk synergy test using cefotaxime, ceftazidime, ceftriaxone, cefotaxime-clavulanic acid, and ceftazidime-clavulanic acid. The results were analysed for frequencies.

Results.

K. pneumoniae isolates showed minimum resistance to imipenem 13% (4/30) followed by amikacin 17% (5/30). There was intermediate resistance to gentamycin 60% (18/30). However, K. pneumoniae showed the highest resistance to piperacillin; 100% (30/30) followed by sulphamethoxazole-trimethoprim and cefepime both showing a percentage of 97% (29/30). Up to 16/30 (53.3%) of K. pneumoniae were positive for ESBL production while 14/30 (46.7%) were negative.
Conclusion.
There was a high prevalence of antibiotic resistant ESBL-producing K pneumoniae isolates from bloodstream infection of patients with features of sepsis in Uganda’s Mulago National Referral Hospital.
Growth kinetics of high-grade serous ovarian cancer using longitudinal clinical data - implications for early detection
Authors: Narayanan Bharath , Buddenkote Thomas , Smith Hayley , Shah Mitul , Freeman Susan , Hulse David , Funingana Gabriel , Alcaraz Marie-Lyne , Ortuzar Mireia-Crispin , Brenton James , Pharoah Paul , Pashayan Nora
Published: November 2024

High-grade serous ovarian cancer (HGSOC) is the most lethal gynaecological cancer with patients routinely diagnosed at advanced stages with widespread disease. Evidence from screening trials indicates that early diagnosis may not reduce cancer-related deaths, possibly due to an underestimation of the true extent of the disease at screening. We aim to characterise the growth kinetics of HGSOC to understand why early detection has failed so far and under what conditions it might prove fruitful.

We analysed a dataset of 597 patients with a confirmed HGSOC diagnosis, and identified 37 cases with serial CT scans. We calculated the growth rates of lesions in the ovaries/pelvis and the omentum and estimated the time to metastasis using a population-level Gompertz model. Finally, we simulated ultrasound and CA125 based screening in a virtual population of patients.

Growing lesions in the ovaries and the omentum doubled in volume every 2.3 months and 2 months respectively. At both sites, smaller lesions grew faster than larger ones. The 12 cases with growing lesions in both disease sites had a median interval of 11.5 months between disease initiation and the onset of metastasis. Our simulations suggested that over 33% of patients would develop metastases before they could be screen detected. The remaining patients provided a median window of opportunity of only 4.7 months to detect the tumours before they metastasised.

Our results suggest that HGSOC lesions have short time to metastasis intervals, preventing effective early detection using current screening approaches.
Tracking Immunity: Increased number of COVID-19 boosters increases the longevity of anti-RBD and anti-RBD neutralizing antibodies
Authors: Hou Ching-Wen , Williams Stacy , Boyle Veronica , Roeder Alexa , Bobbett Bradley , Garcia Izamar , Caruth Giavanna , Magee Mitch , Chung Yunro , Lake Douglas , LaBaer Joshua , Murugan Vel
Published: November 2024

Background/Objectives

Since the World Health Organization declared COVID-19 a pandemic in March 2020, the virus has caused multiple waves of infection globally. Arizona State University (ASU), the largest four-year university in the United States, offers a uniquely diverse setting for assessing immunity within a large community. This study aimed to evaluate SARS-CoV-2 antibody seroprevalence and the effects of infection and vaccination three years into the pandemic.

Methods

A serosurvey was conducted at ASU from January 30 to February 3, 2023. Participants completed questionnaires about demographics, respiratory infection history, symptoms, and COVID-19 vaccination status. Blood samples were analyzed for anti-receptor binding domain (RBD) IgG and anti-nucleocapsid (NC) antibodies, offering a comprehensive view of immunity from both natural infection and vaccination.

Results

The seroprevalence of anti-RBD IgG antibodies was 96.2% (95% CI: 94.8%-97.2%), and 64.9% (95% CI: 61.9%-67.8%) of participants had anti-NC antibodies. Anti-RBD IgG levels correlated strongly with neutralizing antibody levels, and participants who received more vaccine doses showed higher levels of both anti-RBD IgG and neutralizing antibodies. Increasing number of exposures through vaccination and/or infection resulted in higher and long-lasting antibodies.

Conclusion

The high levels of anti-RBD antibodies observed reflect substantial vaccine uptake within this population. Ongoing vaccination efforts, especially as new variants emerge, are essential to maintaining protective antibody levels. These findings underscore the importance of sustained public health initiatives to support broad-based immunity and protection.
Obfuscation via pitch-shifting for balancing privacy and diagnostic utility in voice-based cognitive assessment
Authors: Ahangaran Meysam , Dawalatabad Nauman , Karjadi Cody , Glass James , Au Rhoda , Kolachalama Vijaya B.
Published: November 2024

Introduction

Digital voice analysis is gaining traction as a tool to differentiate cognitively normal from impaired individuals. However, voice data poses privacy risks due to the potential identification of speakers by automated systems.

Methods

We developed a framework that uses weighted linear interpolation of privacy and utility metrics to balance speaker obfuscation and cognitive integrity in cognitive assessments. This framework applies pitch-shifting for speaker obfuscation while preserving cognitive speech features. We tested it on digital voice recordings from the Framingham Heart Study (N=128) and Dementia Bank Delaware corpus (N=85), both containing responses to neuropsychological tests.

Results

The tool effectively obfuscated speaker identity while maintaining cognitive feature integrity, achieving an accuracy of 0.6465 in classifying individuals with normal cognition, mild cognitive impairment, and dementia in the FHS cohort.

Discussion

Our approach enables the development of digital markers for dementia assessment while protecting sensitive personal information, offering a scalable solution for privacy-preserving voice-based diagnostics.
OmniSegger: A time-lapse image analysis pipeline for bacterial cells
Authors: Lo Teresa W. , Cutler Kevin J. , Choi H. James , Wiggins Paul A.
Published: November 2024

Time-lapse microscopy is a powerful tool for studying the cell biology of bacterial cells. The development of pipelines that facilitate the automated analysis of these datasets is a long-standing goal of the field. In this paper, we describeOmniSegger, an updated version of ourSuperSeggerpipeline, developed as an open-source, modular, and holistic suite of algorithms whose input is raw microscopy images and whose output is a wide range of quantitative cellular analyses, including dynamical cell cytometry data and cellular visualizations. The updated version described in this paper introduces two principal refinements: (i) robustness to cell morphologies and (ii) support for a range of common imaging modalities. To demonstrate robustness to cell morphology, we present an analysis of the proliferation dynamics ofEscherichia colitreated with a drug that induces filamentation. To demonstrate extended support for new image modalities, we analyze cells imaged by five distinct modalities: phase-contrast, two brightfield modalities, and cytoplasmic and membrane fluorescence. Together, this pipeline should greatly increase the scope of tractable analyses for bacterial microscopists.
The evolution of irreversible cell differentiation under cell death effect
Authors: Gao Yuanxiao , Zhao Xueyan , Li Caixia
Published: November 2024

Cell differentiation is an important characteristic of multicellular organisms which produce new-typed cells to engage in diverse life functions. Irreversible differentiation, as an important differentiation, describes cells differentiated by determined trajectories to form specialized cell types. It has been found that differentiated cell types often show different death rates. Yet, it is still unclear what role cell death plays in shaping the formation of irreversible cell differentiation. Here, we establish a theoretical model to investigate the impact of cell death on the evolution of irreversible cell differentiation in multicellular organisms. Irreversible differentiation refers to the loss of a cell type's differentiation potential, and it is constructed by the sequences of differentiation probabilities of a cell type across cell divisions. We show that irreversible differentiation is more likely to occur when cell death rates between cell types are linear. Meanwhile, differences in death rates between cell types affect the emergence conditions of irreversible differentiation, whereas no significant impacts on that from equal cell death rates. Additionally, we found that cell death impacts the cell number and cell composition of a mature organism. These findings provide insights into understanding the role of cell death in the formation of cells' irreversible differentiation.
Rapid enzymatic assay for antiretroviral drug monitoring using CRISPR-Cas12a enabled readout
Authors: Singh Maya A. , Chang Megan M. , Wang Qin , Rodgers Catherine , Lutz Barry R. , Olanrewaju Ayokunle O.
Published: November 2024

Maintaining efficacy of human immunodeficiency virus (HIV) medications is challenging among children because of dosing difficulties, the limited number of approved drugs, and low rates of medication adherence. Drug level feedback (DLF) can support dose optimization and timely interventions to prevent treatment failure, but current tests are heavily instrumented and centralized. We developed the REverse-transcriptase ACTivity-crispR (REACTR) assay for rapid measurement of HIV drugs based on the extent of DNA synthesis by HIV reverse transcriptase. CRISPR-Cas enzymes bind to synthesized DNA, triggering collateral cleavage of quenched reporters and generating fluorescence. We measured azidothymidine triphosphate (AZT-TP), a key drug in pediatric HIV treatment, and investigated the impact of assay time and DNA template length on REACTR’s sensitivity. REACTR selectively measured clinically relevant AZT-TP concentrations in the presence of genomic DNA and peripheral blood mononuclear cell lysate. REACTR has the potential to enable rapid point-of-care HIV DLF to improve pediatric HIV care.
FIDDLE: a deep learning method for chemical formulas prediction from tandem mass spectra
Authors: Hong Yuhui , Li Sujun , Ye Yuzhen , Tang Haixu
Published: November 2024

Molecular identification through tandem mass spectrometry is fundamental in metabolomics, with formula identification serving as an initial step in the process. Current computational methods often struggle with accuracy, speed, and scalability for relatively larger molecules, limiting high-throughput workflows. We present FIDDLE (FormulaIDentification byDeepLEarning), a deep learning-based method trained on over 38,000 molecules and 1 million MS/MS spectra from various Quadrupole Time-of-Flight (QTOF) and Orbitrap instruments. FIDDLE accelerates formula identification by more than 10-fold and achieves top-1 and top-5 accuracies of 88.3% and 93.6%, respectively, outperforming state-of-the-art methods based on top-down (SIRIUS) and bottom-up (BUDDY) approaches by over 10%. On external metabolomics datasets, FIDDLE achieves top-3 accuracies of 72.1% (positive ion mode) and 66.2% (negative ion mode), with further improvements to 80.0% and 73.8% when combined with SIRIUS and BUDDY.
Language Models for Molecular Dynamics
Authors: Murtada Mhd Hussein , Brotzakis Z. Faidon , Vendruscolo Michele
Published: November 2024

Molecular Dynamics (MD) simulations provide accurate descriptions of the motions of molecular systems, yet their computational demands pose significant challenges in applications in molecular biology and materials science. Given the success of deep learning methods in a wide range of fields, a timely question concerns whether these methods could be leveraged to improve the efficiency of MD simulations. To investigate this possibility, we introduce Molecular Dynamics Language Models (MDLMs), to enable the generation of MD trajectories. In the present implementation, an MDLM is trained on a short classical MD trajectory of a protein, where structural accuracy is maintained through kernel density estimations derived from extensive MD datasets. We illustrate the application of this MDLM in the case of the determination of the free energy landscape a small protein, showing that this approach makes it possible to discover conformational states undersampled in the training data. These results provide initial evidence for the use of language models for the efficient implementation of molecular dynamics.
Assessment of Workers’ Perception of Occupational Hazards at Nampundwe Mine in Zambia
Authors: Phiri Anthony , Nyirenda Wezi , Phiri Enos , Phiri Maxwell , Muranda Andy , Mulenga Martha , Manchisi James
Published: November 2024

Background

The extent to which Mineworkers perceive hazards at the workplace is important to avoid Mine accidents and thus prevent damage to health, life, and property. However, Mine accidents have increased despite the large investments in health and safety training programs.

Methods

The study used a mixed-method approach to collect data. The study comprised 205 Workers in total, consisting of 8 Managers, 18 Supervisors, 24 Machine Operators, 80 General Miners, and 75 Contractors. These respondents were chosen by using a purposive simplifying procedure. The study used semi-structured interviews, focus group discussions, and document reviews in the collection of data.

Results

Study findings revealed that there was a significantly high impact of occupational health hazards on monthly income towards Contractors (p < 0.001, OR = 0.99, CI = 0.997-0.998). The study findings further reported that Workers at Nampundwe Mine have good to fair knowledge of occupational hazards. Supervisors appeared to have the highest level of awareness among the respondents, fair (38.97%), and good (54.61%). The Contractors had the lowest level of awareness and these were ranked as either fair (37, 05%) or good (18.65%).

It has also revealed that the major causes of accidents are contravening of Safety Rules (38.11%) Falling from Heights (37.52%), Trackless Vehicles (8%), Rock Falling (5.4%), Morning Shifts (4.01%) and Electricity Shocks (6.91%)

Further, the results reported that the major causes of accidents are falling from heights recorded a (37.52%) followed by trackless vehicles at (25.00%), rock falling standing at (16.06%), electricity shock (12.58%), explosion (7.10%), and least flooding at (1.74 %). Additionally, respondents are trained on how to respond to an emergency. And are very much aware of the health and safety measures and all standard operation procedures but rarely follow them when executing tasks.

Conclusions

Our result found Workers have good to fair knowledge of occupational hazards. Supervisors appeared to have the highest level of awareness among the respondents.
Long-telomeropathy is associated with tumor predisposition syndrome
Authors: Allaire Patrick , Mayer John , Moat Luke , Gabor Rachel , Shay Jerry W. , He Jing , Zeng Chenjie , Bastarache Lisa , Hebbring Scott
Published: November 2024

Telomeres protect chromosomal integrity, and telomere length (TL) is influenced by environmental and genetic factors. While short-telomeres are linked to rare telomeropathies, this study explored the hypothesis that a “long-telomeropathy” is associated with a cancer-predisposing syndrome. Using genomic and health data from 113,861 individuals, a trans-ancestry polygenic risk score for TL (PRSTL) was developed. A phenome-wide association study (PheWAS) identified 65 tumor traits linked to elevated PRSTL. Using this result, a trans-ancestry phenotype risk score for a long-TL (PheRSLTL) was develop and validated. Rare variant analyses revealed 13 genes associated with PheRSLTL. Individuals who were carriers of these rare variants had a predisposition for long-TL validating original hypothesis. Most of these genes were new to both cancer and telomere biology. In conclusion, this study identified a novel tumor-predisposing syndrome shaped by both common and rare genetic variants, broadening the understanding of telomeropathies to those with a predisposition for long telomeres.