bluuebunny/crossref_metadata_2025 huggingface dataset:
Ruptured vertebrobasilar junction aneurysm supplied by reversed flow from the anterior spinal artery: Illustrative case report
Authors: Gonce Collin E , Prather Kiana Y , Bauer Andrew M , Shakir Hakeem J , Jen Shyian S , Graffeo Christopher S
Published: August 2023

Background and Importance

In patients with vertebral artery (VA) occlusion, spontaneous flow reversal may occur in the anterior spinal artery (ASA) as a source of compensatory supply to the posterior circulation. Turbulent flow and increased flux through these small arteries may predispose to luminal damage and intracranial aneurysm formation. We report a novel case of a ruptured ASA–VA junction aneurysm in a patient with chronic bilateral VA occlusion, successfully treated with endovascular embolization.

Clinical Presentation

A 62-year-old female with uncontrolled hypertension presented with acute-onset headache, emesis, neck stiffness, and decreased level of consciousness. Head computed tomography demonstrated diffuse cisternal subarachnoid hemorrhage with intraventricular extension and ventriculomegaly. Computed tomography angiography showed left VA atresia and chronic right VA occlusion just distal to the posterior inferior cerebellar artery origin, as well as a complex, bilobed aneurysm at the ASA–VA junction. Angiography demonstrated flow reversal from the ASA into the distal stump of the occluded right VA, which in turn filled the aneurysm. Of note, the patient's posterior circulation was predominantly supplied by the dilated ASA, and associated collaterals from ASA and right VA stump. The aneurysm was accessed and embolized using superselective microcatheterization over a soft microguidewire through the right cervical VA perforators supplying retrograde flow into and through the ASA.

Conclusion

ASA–VA aneurysms are exceedingly rare, and generally associated with atypical flow dynamics. Dynamic treatment strategies may be needed, especially in the setting of subarachnoid hemorrhage.
The effect of occlusion location and technique in mechanical thrombectomy for minor stroke
Authors: Abecassis Isaac Josh , Almallouhi Eyad , Chalhoub Reda M. , Helal Ahmed , Naidugari Janki R. , Kasab Sami Al , Bass Eric , Ding Dale , Saini Vasu , Burks Joshua D. , Maier Ilko L. , Jabbour Pascal , Kim Joon-Tae , Wolfe Stacey , Rai Ansaar , Psychogios Marios-Nikos , Samaniego Edgar , Arthur Adam S. , Yoshimura Shinichi , Howard Brian , Alawieh Ali , Fragata Isabel , Cuellar Hugo , Polifka Adam , Mascitelli Justin , Osbun Joshua , Crosa Roberto , Matouk Charles , Park Min S. , Levitt Michael R. , Dumont Travis , Williamson Richard W. , Spiotta Alejandro M. , Starke Robert M.
Published: August 2023

Introduction

Endovascular mechanical thrombectomy (MT) is an established treatment for large vessel occlusion strokes with a National Institutes of Health Stroke Scale (NIHSS) score of 6 or higher. Data pertaining to minor strokes, medium, or distal vessel occlusions, and most effective MT technique is limited and controversial.

Methods

A multicenter retrospective study of all patients treated with MT presenting with NIHSS score of 5 or less at 29 comprehensive stroke centers. The cohort was dichotomized based on location of occlusion (proximal vs. distal) and divided based on MT technique (direct aspiration first-pass technique [ADAPT], stent retriever [SR], and primary combined [PC]). Outcomes at discharge and 90 days were compared between proximal and distal occlusion groups, and across MT techniques.

Results

The cohort included 759 patients, 34% presented with distal occlusion. Distal occlusions were more likely to present with atrial fibrillation (p = 0.008) and receive IV tPA (p = 0.001). Clinical outcomes at discharge and 90 days were comparable between proximal and distal groups. Compared to SR, patients managed with ADAPT were more likely to have a modified Rankin Scale of 0–2 at discharge and at 90 days (p = 0.024 and p = 0.013). Primary combined compared to ADAPT, prior stroke, multiple passes, older age, and longer procedure time were independently associated with worse clinical outcome, while successful recanalization was positively associated with good clinical outcomes.

Conclusions

Proximal and distal occlusions with low NIHSS have comparable outcomes and safety profiles. While all MT techniques have a similar safety profile, ADAPT was associated with better clinical outcomes at discharge and 90 days.
Further evidence for the role of temporal contiguity as a determinant of overshadowing
Authors: Alcalá José A , Ogallar Pedro M , Prados José , Urcelay Gonzalo P
Published: August 2023

Three experiments explored whether weakening temporal contiguity between auditory cues and an aversive outcome attenuated cue competition in an avoidance learning task with human participants. Overall, with strong temporal contiguity between auditory cues and the outcome during training (the offset of the predictive auditory signals concurred with the onset of the outcome), the target cue trained as part of a compound yielded less avoidance behaviour than the control cue trained alone, an instance of overshadowing. However, weakening temporal contiguity during training (inserting a 5-s trace) attenuated overshadowing, resulting in similar avoidance behaviour in response to the control and target cues. These results provide evidence that, as predicted by a recent modification of Pearce’s configural theory, temporal contiguity is critical for determining cue competition.
Mental pictures, structural constraints: Kenneth N. Waltz’s approach to theory
Authors: Güner Serdar Ş
Published: August 2023

The aim of this article is to develop Kenneth N. Waltz’s conceptualization of system structures based on the distribution of capabilities to those described by two traits at system-level: the distribution of capabilities across states and states’ geographic positions with respect to each other, that is, the contiguity configuration. The development generates taxonomies of structures evaluated as mental pictures that guide, organize, and channel thoughts by identifying the ways system structures constrain international interactions. Mental pictures are argued to derive from a multiplicity of interrelated neurophysiological processes of the brain according to functionalism which is a monist doctrine of the philosophy of mind. Mental pictures establish structural constraints as products of an algorithm based on realism and system theory depicting a neo-Kantian view of how our minds impose order on sensory data.
Cryptotanshinone, a Potential SIRT3 Inhibitor, Suppresses Colorectal Cancer Proliferation in vitro and in vivo
Authors: Song Dimeng , Fang Xiaoxue , Sun Zhiyuan , Qiu Zhidong , Liu Da , Luo Haoming , Jin Ye , Wu Donglu
Published: August 2023

Cryptotanshinone (CPT) is the main pharmacologically active component of Salvia miltiorrhiza Bunge, and has been demonstrated to have inhibitory effects on a variety of cancer cell types. However, the target(s) of CPT in colorectal cancer (CRC) cells are still to be identified. The aim of this study was to investigate the molecular mechanism of CPT-induced apoptosis in CRC cells. Transcriptome sequencing revealed that 1234 genes were differentially expressed in CPT-treated SW480 cells compared with vehicle control, which were associated with signaling pathways such as PI3K/AKT, Pathways in cancer and biological processes include cell proliferation and mitochondrial function. CCK-8, colony formation assay, and CRC tumor xenograft models suggested that CPT suppressed the colony formation ability and inhibited proliferation of CRC cells in vitro and in vivo, while flow cytometry indicated that CPT arrested the cell cycle in S phase. JC-1, Hoechst and Western blot analysis indicated that CPT promoted apoptosis in CRC cells and triggered alterations in mitochondrial membrane potential. In addition, database analysis showed that high SIRT3 expression in CRC and high SIRT3 expression in CRC was associated with shorter survival times. Immunofluorescence, Western blot, and molecular docking confirmed that CPT was able to target SIRT3 and downregulate SIRT3 protein levels in a concentration-dependent manner. In summary, CPT inhibits SIRT3 protein expression and inhibits CRC proliferation in vitro and in vivo.
Severe Mimic of Transverse Myelitis - Spontaneous Non-Traumatic Intramedullary Hematomyelia: A Case Report
Authors: Simon Devin
Published: August 2023

Spinal cord hemorrhage remains an uncommon vascular pathology with no standard approach to treatment. Intramedullary hematomyelia is the rarest subtype and has only been described in case reports, making it a diagnosis easier to miss. A 55-year-old male with history of polysubstance abuse presented for abrupt onset non-traumatic back pain that progressed over several days evolving into paraplegia, sensory loss up to the T3 dermatome, and incontinence of bowel and bladder. His MRI imaging of the cervical and thoracic spine was concerning for a T1 and T2 hyperintense lesion extending from the internal medulla to the upper thoracic spine causing edema. The initial differential diagnosis, based on history and progressive neurologic decline, included a longitudinally extensive transverse mellitus of unclear etiology. He received high dose steroids and plasma exchange without any clinical improvement. An extensive autoimmune, inflammatory, infectious, and demyelinating workup via serum and CSF analysis was unremarkable. He was transferred to a tertiary facility, where repeat MRI spinal imaging included GRE sequences that was significant for increased susceptibility. MRA imaging of the spine was completed showing no vascular malformation. Overall, the diagnosis of hematomyelia was felt to be most likely. Despite aggressive inpatient rehabilitation, the patient remains paraplegic and requires long term management consistent with severe spinal cord injury. This case highlights the importance of recognizing vascular syndromes as a cause of acute myelopathy, understanding the imaging findings of blood breakdown products on MRI, and the desperate need for successful therapeutic strategies to combat a potentially devastating neurologic process.
Impact of the COVID-19 Pandemic on Inpatient Utilization for Acute Neurologic Disease
Authors: Yoo Alexander , Guterman Elan L. , Hwang David Y. , Holloway Robert G. , George Benjamin P.
Published: August 2023

Background and Objective: The initial months of the Corona Virus 2019 (COVID-19) pandemic resulted in decreased hospitalizations. We aimed to describe differences in hospitalizations and related procedures across neurologic disease. Methods: In our retrospective observational study using the California State Inpatient Database and state-wide population-level estimates, we calculated neurologic hospitalization rates for a control period from January 2019 to February 2020 and a COVID-19 pandemic period from March to December 2020. We calculated incident rate ratios (IRR) for neurologic hospitalizations using negative binomial regression and compared relevant procedure rates over time. Results: Population-based neurologic hospitalization rates were 29.1 per 100,000 (95% CI 26.9–31.3) in April 2020 compared to 43.6 per 100,000 (95% CI 40.4–46.7) in January 2020. Overall, the pandemic period had 13% lower incidence of neurologic hospitalizations per month (IRR 0.87, 95% CI 0.86-0.89). The smallest decreases were in neurotrauma (IRR 0.92, 95% CI 0.89–0.95) and neuro-oncologic cases (IRR 0.93, 95% CI 0.87–0.99). Headache admissions experienced the greatest decline (IRR 0.62, 95% CI 0.58–0.66). For ischemic stroke, greater rates of endovascular thrombectomy (5.6% vs 5.0%; P < .001) were observed in the pandemic. Among all neurologic disease, greater rates of gastrostomy (4.0% vs 3.5%; P < .001), intubation/mechanical ventilation (14.3% vs 12.9%, P < .001), and tracheostomy (1.4 vs 1.2%; P < .001) were observed during the pandemic. Conclusions: During the first months of the COVID-19 pandemic there were fewer hospitalizations to varying degrees for all neurologic diagnoses. Rates of procedures indicating severe disease increased. Further study is needed to determine the impact on triage, patient outcomes, and cost consequences.
Early Complication Rates Are Equivalent Between Isolated Cartilage Restoration and Concomitant Cartilage Restoration and Osteotomy of the Knee
Authors: Bohlen Hunter , Karasavvidis Theofilos , Wen Deborah , Wong Francis K.L. , Wang Dean
Published: August 2023

Objective

Realignment osteotomy performed concomitantly with cartilage restoration typically requires early restricted weightbearing and can add significant morbidity, potentially leading to an increased risk of early perioperative complications. The purpose of this study was to compare the 30-day complication rates after isolated cartilage restoration (ICR) versus concomitant cartilage restoration and osteotomy (CRO) using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database.

Design

NSQIP registries between 2006 and 2019 were queried using Current Procedural Terminology codes to identify patients undergoing ICR (autologous chondrocyte implantation, osteochondral autograft transfer, or osteochondral allograft transplantation) and CRO (with concomitant high tibial osteotomy, distal femoral osteotomy, and/or tibial tubercle osteotomy). Complications rates between treatment groups were compared using multivariate logistic regression analyses adjusted for sex, age, steroid use, and respiratory status.

Results

A total of 773 ICR and 97 CRO surgical procedures were identified. Mean patient ages were 35.9 years for the ICR group and 31.2 years for the CRO group. Operative time was significantly longer in the CRO group (170.8 min) compared with the ICR group (97.8 min). Multivariate analysis demonstrated no significant differences in rates of PE, VTE, and all-cause readmission between the ICR and CRO groups. No events of wound disruption, SSI and reoperation were found in the CRO group, while the ICR group was characterized by low rates of wound disruption, reoperation, and SSI (<1.1%).

Conclusions

These findings further support concomitant osteotomy with cartilage restoration when appropriate and aid surgeons in the preoperative counseling of patients undergoing cartilage restoration treatment.
Comparison of Hydrogel-Based Autologous Chondrocyte Implantation Versus Microfracture: A Propensity Score Matched-Pair Analysis
Authors: Niemeyer Philipp , Angele Peter , Spiro Robert C. , Kirner Alexandra , Gaissmaier Christoph
Published: August 2023

Background:

Few studies exist for large defects comparing matrix-associated autologous chondrocyte implantation (M-ACI) with other cartilage repair methods due to the limited availability of suitable comparator treatments.

Purpose:

To compare the clinical efficacy of a novel hydrogel-based M-ACI method (NOVOCART Inject plus) versus microfracture (MFx) in patients with knee cartilage defects.

Study Design:

Cohort study; Level of evidence, 3.

Methods:

Propensity score matched-pair analysis was used to compare the 24-month outcomes between the M-ACI treatment group from a previous single-arm phase 3 study and the MFx control group from another phase 3 study. Patients were matched based on preoperative Knee injury and Osteoarthritis Outcomes Score (KOOS), symptom duration, previous knee surgeries, age, and sex, resulting in 144 patients in the matched-pair set (72 patients per group). The primary endpoint was the change in least-squares means (ΔLSmeans) for the KOOS from baseline to the 24-month assessment.

Results:

Defect sizes in the M-ACI group were significantly larger than in the MFx group (6.4 versus 3.7 cm2). Other differences included defect location (no patellar or tibial defects in the MFx group), number of defects (33.3% with 2 defects in the M-ACI group versus 9.7% in the MFx group), and defect cause (more patients with degenerative lesions in the M-ACI group). The M-ACI group had higher posttreatment KOOS (M-ACI versus MFX: 81.8 ± 16.8 versus 73.0 ± 20.6 points) and KOOS ΔLSmeans from baseline to 24 months posttreatment (M-ACI versus MFX: 36.9 versus 26.9 points). Treatment contrasts in KOOS ΔLSmeans from baseline indicated statistical significance in favor of M-ACI from 3 to 24 months posttreatment ( P = .0026). Significant and clinically meaningful differences in favor of M-ACI at 24 months were also found regarding International Knee Documentation Committee (IKDC) score ΔLSmeans from baseline (37.8 versus 30.4 points; P = .0334), KOOS responder rates at 24 months (≥10-point improvement from baseline; 94.4% versus 65.3%; P < .0001), IKDC responder rates at 24 months (>20.5-point improvement from baseline; 83.3% versus 61.1%, P = .0126) and MOCART (Magnetic Resonance Observation of Cartilage Repair Tissue) score in a subgroup of patients (LS means, 86.9 versus 69.1; P = .0096).

Conclusion:

In this exploratory analysis, M-ACI using an in situ crosslinked hydrogel demonstrated superior clinical and structural (MOCART) 24-month outcomes compared with MFx in patients with knee cartilage defects.
Mesenchymal Hamartoma With Elevated Alpha-Fetoprotein: A Diagnostic Pitfall
Authors: Naggar Amine , Andour Hajar , Bensaghir Hamza , Kabila Badr , Ben Driss Chaimae , El Aouni Soukaina , Ochan Monim , Kisra Mounir , Lamalmi Najat , El Haddad Siham , Allali Nazik , Chat Latifa
Published: August 2023

Mesenchymal hamartoma (MH) is a benign liver tumor accounting for 3% to 8% of all liver tumors in children, commonly manifesting before 3 years of life. Distinguishing MH from hepatoblastoma and other liver tumors relies on imaging and alpha-fetoprotein (which is usually within normal range in MH), before histologic examination. We report a case of a hepatic MH associated with elevated alpha-fetoprotein, leading to a misdiagnosis of hepatoblastoma and the administration of chemotherapy. We draw the attention to the diagnostic difficulty and pitfalls related to alpha-fetoprotein elevation in the setting of a liver tumor, and we highlight the importance of imaging and histology in establishing the diagnosis.
Impact of Prefilled Syringes and Masking on Postintravitreal Injection Endophthalmitis
Authors: Louis Abigail M. , Ali Amna M. , Patel Sagar B. , Fan Kenneth C. , Rahman Effie Z. , Pearce William A. , Trejo Corona Stephanie , Villanueva Boone Cecilia , Yu Hannah J. , Wykoff Charles C.
Published: August 2023

Purpose: To compare rates of endophthalmitis (1) following intravitreal injection of antivascular endothelial growth factor therapies with glass-vial preparation (GVP) vs prefilled syringes (PFS) and (2) before and after masking protocols were implemented. Methods: Medical records within a multicenter retina practice in Houston, Texas, from January 2015 to August 2021 were retrospectively reviewed. The primary outcome was rate of endophthalmitis after intravitreal injection. Results: A total of 307 349 injections were performed during the study period and 101 cases of endophthalmitis were identified (0.033%). PFS use was associated with a decreased risk of endophthalmitis (relative risk [RR], 0.320; 95% CI, 0.198-0.518, P < .001); 54 cases of endophthalmitis occurred in the GVP group of aflibercept and ranibizumab (0.052%) compared with 24 in the PFS group (0.017%). There was no difference in the endophthalmitis rates with or without universal masking (RR, 0.953; 95% CI 0.616-1.473, P = .91). Discussion: PFS use was associated with a significant reduction in the rate of endophthalmitis while the use of surgical face masks did not appear to significantly impact the rate of endophthalmitis.
Targeting cancer hallmark vulnerabilities in hematologic malignancies by interfering with Hedgehog/GLI signaling
Authors: Krenn Peter W. , Aberger Fritz
Published: August 2023

Understanding the genetic alterations, disrupted signaling pathways, and hijacked mechanisms in oncogene-transformed hematologic cells is critical for the development of effective and durable treatment strategies against liquid tumors. In this review, we focus on the specific involvement of the Hedgehog (HH)/GLI pathway in the manifestation and initiation of various cancer features in hematologic malignancies, including multiple myeloma, T- and B-cell lymphomas, and lymphoid and myeloid leukemias. By reviewing canonical and noncanonical, Smoothened-independent HH/GLI signaling and summarizing preclinical in vitro and in vivo studies in hematologic malignancies, we elucidate common molecular mechanisms by which HH/GLI signaling controls key oncogenic processes and cancer hallmarks such as cell proliferation, cancer stem cell fate, genomic instability, microenvironment remodeling, and cell survival. We also summarize current clinical trials with HH inhibitors and discuss successes and challenges, as well as opportunities for future combined therapeutic approaches. By providing a bird's eye view of the role of HH/GLI signaling in liquid tumors, we suggest that a comprehensive understanding of the general oncogenic effects of HH/GLI signaling on the formation of cancer hallmarks is essential to identify critical vulnerabilities within tumor cells and their supporting remodeled microenvironment, paving the way for the development of novel and efficient personalized combination therapies for hematologic malignancies.
Fractionated vs single-dose gemtuzumab ozogamicin with determinants of benefit in older patients with AML: the UK NCRI AML18 trial
Authors: Freeman Sylvie D. , Thomas Abin , Thomas Ian , Hills Robert K. , Vyas Paresh , Gilkes Amanda , Metzner Marlen , Jakobsen Niels Asger , Kennedy Alison , Moore Rachel , Almuina Nuria Marquez , Burns Sarah , King Sophie , Andrew Georgia , Gallagher Kathleen M. E. , Sellar Rob S. , Cahalin Paul , Weber Duruta , Dennis Mike , Mehta Priyanka , Knapper Steven , Russell Nigel H.
Published: August 2023

Addition of gemtuzumab ozogamicin (GO) to induction chemotherapy improves outcomes in older patients with acute myeloid leukemia (AML), but it is uncertain whether a fractionated schedule provides additional benefit to a single dose. We randomized 852 older adults (median age, 68-years) with AML/high-risk myelodysplasia to GO on day 1 (GO1) or on days 1 and 4 (GO2) of course 1 induction. The median follow-up period was 50.2 months. Although complete remission (CR) rates after course 1 did not significantly differ between arms (GO2, 63%; GO1, 57%; odds ratio [OR], 0.78; P = .08), there were significantly more patients who achieved CR with a measurable residual disease (MRD)<0.1% (50% vs 41%; OR, 0.72; P = .027). This differential MRD reduction with GO2 varied across molecular subtypes, being greatest for IDH mutations. The 5-year overall survival (OS) was 29% for patients in the GO2 arm and 24% for those in the GO1 arm (hazard ratio [HR], 0.89; P = .14). In a sensitivity analysis excluding patients found to have adverse cytogenetics or TP53 mutations, the 5-year OS was 33% for GO2 and 26% for GO1 (HR, 0.83; P = .045). In total, 228 (27%) patients received an allogeneic transplantation in first remission. Posttransplant OS was superior in the GO2 arm (HR, 0.67; P = .033); furthermore, the survival advantage from GO2 in the sensitivity analysis was lost when data of patients were censored at transplantation. In conclusion, GO2 was associated with a greater reduction in MRD and improved survival in older adults with nonadverse risk genetics. This benefit from GO2 was dependent on allogeneic transplantation to translate the better leukemia clearance into improved survival. This trial was registered at www.isrctn.com as #ISRCTN 31682779.
Malignancy-associated hemophagocytic lymphohistiocytosis in Sweden: incidence, clinical characteristics, and survival
Authors: Löfstedt Alexandra , Jädersten Martin , Meeths Marie , Henter Jan-Inge
Published: August 2023

We evaluated malignancy-associated hemophagocytic lymphohistiocytosis (mal-HLH) in Sweden regarding population-based incidence, clinical features, and survival. From 1997 to 2018, we identified 307 adults (≥18 years old) and 9 children (209 males, 107 females; P < .001) with both an HLH-related diagnosis and malignant disease, corresponding to 0.19 per 100 000 adults annually (0.15/100 000 for the entire population), increasing from 0.026 (1997-2007) to 0.34 (2008-2018) (P < .001). In the latest 7-year period (2012-2018), the annual incidence was 0.45 per 100 000 adults (n = 246). This incidence varied between the 6 health care regions in Sweden, from 0.18 to 0.71 (Region Stockholm) per 100 000 adults annually (P < .001), likely due to variable awareness. Mal-HLH was reported in 0.6% of all hematological malignancies, with the highest proportion (2.5%) in young males. Among the 316 patients, the 1-month probability of survival, likely representing the HLH episode, increased significantly from 52% (95% confidence interval [CI], 40-63) (1997-2007) to 71% (95% CI, 65-76) (2008-2018), whereas 2-year survival remained poor (25%; 95% CI, 20-30). Altogether, 52% were lymphomas, 29% leukemias, 8% other hematological malignancies, and 11% solid tumors. Males were more affected than females by mal-HLH, also taking the over-representation of males with hematological malignancies into account (P = .0012). Validation by medical-file reviews revealed 13% over-reporting of HLH. We conclude that the annual mal-HLH incidence has increased 10-fold and was at least 0.71 per 100 000 adults from 2012 to 2018, that is, 0.62 per 100 000 adults considering 13% estimated HLH over-reporting, and that early survival improved significantly, likely due to increased awareness and more HLH-directed therapy.
Genetic alterations and MRD refine risk assessment for KMT2A-rearranged B-cell precursor ALL in adults: a GRAALL study
Authors: Kim Rathana , Bergugnat Hugo , Pastoret Cédric , Pasquier Florence , Raffoux Emmanuel , Larcher Lise , Passet Marie , Grardel Nathalie , Delabesse Eric , Kubetzko Susanne , Caye-Eude Aurélie , Meyer Claus , Marschalek Rolf , Lafage-Pochitaloff Marine , Thiebaut-Bertrand Anne , Balsat Marie , Escoffre-Barbe Martine , Blum Sabine , Baumann Michael , Banos Anne , Straetmans Nicole , Gallego-Hernanz Maria-Pilar , Chalandon Yves , Graux Carlos , Soulier Jean , Leguay Thibaut , Hunault Mathilde , Huguet Françoise , Lhéritier Véronique , Dombret Hervé , Boissel Nicolas , Clappier Emmanuelle
Published: August 2023

KMT2A-rearranged (KMT2A-r) B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is widely recognized as a high-risk leukemia in both children and adults. However, there is a paucity of data on adults treated in recent protocols, and the optimal treatment strategy for these patients is still a matter of debate. In this study, we set out to refine the prognosis of adult KMT2A-r BCP-ALL treated with modern chemotherapy regimen and investigate the prognostic impact of comutations and minimal residual disease (MRD). Of 1091 adult patients with Philadelphia-negative BCP-ALL enrolled in 3 consecutive trials from the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL), 141 (12.9%) had KMT2A-r, with 5-year cumulative incidence of relapse (CIR) and overall survival (OS) rates of 40.7% and 53.3%, respectively. Molecular profiling highlighted a low mutational burden in this subtype, reminiscent of infant BCP-ALL. However, the presence of TP53 and/or IKZF1 alterations defined a subset of patients with significantly poorer CIR (69.3% vs 36.2%; P = .001) and OS (28.1% vs 60.7%; P = .006) rates. Next, we analyzed the prognostic implication of MRD measured after induction and first consolidation, using both immunoglobulin (IG) or T-cell receptor (TR) gene rearrangements and KMT2A genomic fusion as markers. In approximately one-third of patients, IG/TR rearrangements were absent or displayed clonal evolution during the disease course, compromising MRD monitoring. In contrast, KMT2A-based MRD was highly reliable and strongly associated with outcome, with early good responders having an excellent outcome (3-year CIR, 7.1%; OS, 92.9%). Altogether, our study reveals striking heterogeneity in outcomes within adults with KMT2A-r BCP-ALL and provides new biomarkers to guide risk-based therapeutic stratification.
A novel GATA2 distal enhancer mutation results in MonoMAC syndrome in 2 second cousins
Authors: West Robert R. , Bauer Thomas R. , Tuschong Laura M. , Embree Lisa J. , Calvo Katherine R. , Tillo Desiree , Davis Joie , Holland Steven M. , Hickstein Dennis D.
Published: August 2023

Mutations in the transcription factor GATA2 can cause MonoMAC syndrome, a GATA2 deficiency disease characterized by several findings, including disseminated nontuberculous mycobacterial infections, severe deficiencies of monocytes, natural killer cells, and B lymphocytes, and myelodysplastic syndrome. GATA2 mutations are found in ∼90% of patients with a GATA2 deficiency phenotype and are largely missense mutations in the conserved second zinc-finger domain. Mutations in an intron 5 regulatory enhancer element are also well described in GATA2 deficiency. Here, we present a multigeneration kindred with the clinical features of GATA2 deficiency but lacking an apparent GATA2 mutation. Whole genome sequencing revealed a unique adenine-to-thymine variant in the GATA2 –110 enhancer 116,855 bp upstream of the GATA2 ATG start site. The mutation creates a new E-box consensus in position with an existing GATA-box to generate a new hematopoietic regulatory composite element. The mutation segregates with the disease in several generations of the family. Cell type–specific allelic imbalance of GATA2 expression was observed in the bone marrow of a patient with higher expression from the mutant-linked allele. Allele-specific overexpression of GATA2 was observed in CRISPR/Cas9-modified HL-60 cells and in luciferase assays with the enhancer mutation. This study demonstrates overexpression of GATA2 resulting from a single nucleotide change in an upstream enhancer element in patients with MonoMAC syndrome. Patients in this study were enrolled in the National Institute of Allergy and Infectious Diseases clinical trial and the National Cancer Institute clinical trial (both trials were registered at www.clinicaltrials.gov as #NCT01905826 and #NCT01861106, respectively).
Understanding the process of improving accessibility and affordability of inter-municipal bus transport system
Authors: Mutiganda Jean C. , Skoog Matti , Igudia Eghosa
Published: August 2023

This paper examines the ways an inter-municipality bus system for passengers improved its accessibility and affordability for end-users at regional level. Using archetype theory, we conducted a case-study in FÖLI, a not-for-profit organization tasked with collective transport of passengers by bus in Southwest Finland. We find that FÖLI implemented a radical revolutionary change by introducing a new framework for the carriage of passengers by bus at a regional level, in which a zone free and flat fare policy applies. The sequence of change became central; with a continuous reorientation linearity aiming to improve the accessibility and affordability of collective transport by bus for commuters. The paper contributes to archetype theory by examining the relevance of accessibility and affordability in the configuration process of designing and implementing change, and extending knowledge in this area. Specifically, for the first time, our research shows the way in which FÖLI used the accessibility and affordability policy as an interpretative scheme to design and implement the change process successfully. The practical implication is that municipalities understood the relevance of improving collective transport infrastructures (roads, systems and technologies) to attract commuters as a way of saving total costs to fund underperforming buslines.
A systematic analysis of the phloem protein 2 (PP2) proteins in Gossypium hirsutum reveals that GhPP2-33 regulates salt tolerance
Authors: Wei Fei , Chen Pengyun , Jian Hongliang , Guo Xiaohao , Lv Xiaoyan , Lian Boying , Sun Mengxi , An Li , Dang Xinyu , Yang Miaoqian , Wu Hongmei , Zhang Nan , Wu Aimin , Wang Hantao , Ma Liang , Fu Xiaokang , Lu Jianhua , Yu Shuxun , Wei Hengling
Published: August 2023

Background

Phloem protein 2 (PP2) proteins play a vital role in the Phloem-based defense (PBD) and participate in many abiotic and biotic stress. However, research on PP2 proteins in cotton is still lacking.

Results

A total of 25, 23, 43, and 47 PP2 genes were comprehensively identified and characterized in G.arboretum, G.raimondii, G.barbadense, and G.hirsutum. The whole genome duplication (WGD) and allopolyploidization events play essential roles in the expansion of PP2 genes. The promoter regions of GhPP2 genes contain many cis-acting elements related to abiotic stress and the weighted gene co-expression network analysis (WGCNA) analysis displayed that GhPP2s could be related to salt stress. The qRT-PCR assays further confirmed that GhPP2-33 could be dramatically upregulated during the salt treatment. And the virus-induced gene silencing (VIGS) experiment proved that the silencing of GhPP2-33 could decrease salt tolerance.

Conclusions

The results in this study not only offer new perspectives for understanding the evolution of PP2 genes in cotton but also further explore their function under salt stress.
Oral microbiome homogeneity across diverse human groups from southern Africa: first results from southwestern Angola and Zimbabwe
Authors: Araújo Vítor , Fehn Anne-Maria , Phiri Admire , Wills Jeffrey , Rocha Jorge , Gayà-Vidal Magdalena
Published: August 2023

Background

While the human oral microbiome is known to play an important role in systemic health, its average composition and diversity patterns are still poorly understood. To gain better insights into the general composition of the microbiome on a global scale, the characterization of microbiomes from a broad range of populations, including non-industrialized societies, is needed. Here, we used the portion of non-human reads obtained through an expanded exome capture sequencing approach to characterize the saliva microbiomes of 52 individuals from eight ethnolinguistically diverse southern African populations from Angola (Kuvale, Kwepe, Himba, Tjimba, Kwisi, Twa, !Xun) and Zimbabwe (Tshwa), including foragers, food-producers, and peripatetic groups (low-status communities who provide services to their dominant neighbors).

Results

Our results indicate that neither host genetics nor livelihood seem to influence the oral microbiome profile, withNeisseria,Streptococcus,Prevotella,Rothia, andPorphyromonasbeing the five most frequent genera in southern African groups, in line with what has been shown for other human populations. However, we found that some Tshwa and Twa individuals display an enrichment of pathogenic genera from theEnterobacteriaceaefamily (i.e.Enterobacter,Citrobacter,Salmonella) of theProteobacteriaphylum, probably reflecting deficient sanitation and poor health conditions associated with social marginalization.

Conclusions

Taken together, our results suggest that socio-economic status, rather than ethnolinguistic affiliation or subsistence mode, is a key factor in shaping the salivary microbial profiles of human populations in southern Africa.
Self-reported musculoskeletal disorders and associated factors among HIV/AIDS patients following ART at University of Gondar Comprehensive Specialized Hospital, Gondar, Ethiopia, 2021: Aa cross-sectional study design
Authors: Kibret Alemu Kassaw , Mekie Yitayal Melisew , Eriku Getachew Azeze , Gashaw Moges , Yalew Ermias Solomon , Weldetsadik Fkrte Kebede
Published: August 2023

Background

Musculoskeletal disorders is an inflammatory, degenerative diseases and disorders that cause pain and functional impairments. Musculoskeletal disorders are common and the major global health concern among people with human immunodeficiency virus/acquired immunodeficiency syndrome which causes physical disability. Despite, it is a recognized health problem among human immunodeficiency virus-positive patients, there is a lack of data on musculoskeletal disorders among patients following anti-retroviral therapy in sub-Saharan Africa, particularly Ethiopia. Therefore, the main aim of the study was to assess the prevalence and associated factors of musculoskeletal disorders among adult human immunodeficiency virus-positive patients following anti-retroviral therapy.

Method

An institutional-based cross-sectional study was conducted from September 1st to October 1st, 2021 at University of Gondar Comprehensive Specialized Hospital, Gondar, Ethiopia. The data was collected through an interview-administered questionnaire and patient medical record review of 324 participants. Binary logistic regression was used to identify associated risk factors of musculoskeletal disorders. The strength of the association was detected by the adjusted odds ratio and P-value.

Result

The annual prevalence of musculoskeletal disorders among participants was 158 (48.5%) with [95% CI: 43%, 54%], opportunistic infection [AOR, 10.43; 95% CI = 2.76–42.25], type of ART medication used, CD4-count [AOR, 0.13; 95% CI 0.03–0.85], and change in anti-retroviral therapy regimen change [AOR, 8.14; 95%CI 2.06–32.09] were significantly associated with musculoskeletal disorders.

Conclusion

The prevalence of musculoskeletal disorders was moderate. Recent CD4 count, opportunistic infection, antiretroviral therapy regime at initiation, and anti-retroviral therapy regime change were significantly associated with musculoskeletal disorder. A multidisciplinary approach is required for preventing and treating musculoskeletal disorders among human immunodeficiency virus-positive patients following anti-retroviral therapy.
Dose finding study for unilobar radioembolization using holmium-166 microspheres to improve resectability in patients with HCC: the RALLY protocol
Authors: Andel Daan , Lam Marnix G. E. H. , de Bruijne Joep , Smits Maarten L. J. , Braat Arthur J. A. T. , Moelker Adriaan , Vegt Erik , Ruiter Simeon J. S. , Noordzij Walter , Grazi Gianluca , Vallati Giulio E. , Bennink Roel J. , van Delden Otto M. , Kranenburg Onno W. , Ijzermans Jan N. M. , Nijkamp Maarten W. , Erdmann Joris I. , Sciuto Rosa , Hagendoorn Jeroen , Borel Rinkes Inne H. M.
Published: August 2023

Background

High dose unilobar radioembolization (also termed ‘radiation lobectomy’)—the transarterial unilobar infusion of radioactive microspheres as a means of controlling tumour growth while concomitantly inducing future liver remnant hypertrophy—has recently gained interest as induction strategy for surgical resection. Prospective studies on the safety and efficacy of the unilobar radioembolization-surgery treatment algorithm are lacking. The RALLY study aims to assess the safety and toxicity profile of holmium-166 unilobar radioembolization in patients with hepatocellular carcinoma ineligible for surgery due to insufficiency of the future liver remnant.

Methods

The RALLY study is a multicenter, interventional, non-randomized, open-label, non-comparative safety study. Patients with hepatocellular carcinoma who are considered ineligible for surgery due to insufficiency of the future liver remnant (< 2.7%/min/m2 on hepatobiliary iminodiacetic acid scan will be included. A classical 3 + 3 dose escalation model will be used, enrolling three to six patients in each cohort. The primary objective is to determine the maximum tolerated treated non-tumourous liver-absorbed dose (cohorts of 50, 60, 70 and 80 Gy). Secondary objectives are to evaluate dose–response relationships, to establish the safety and feasibility of surgical resection following unilobar radioembolization, to assess quality of life, and to generate a biobank.

Discussion

This will be the first clinical study to assess the unilobar radioembolization-surgery treatment algorithm and may serve as a stepping stone towards its implementation in routine clinical practice.

Trial registration

Netherlands Trial Register NL8902, registered on 2020–09-15.
Acute exacerbation of ocular graft-versus-host disease and anterior uveitis after COVID-19 vaccination
Authors: Lin Chen-Yu , Chien Hung-Jen
Published: August 2023

Background

To report a case of simultaneous occurrence of acute exacerbation of ocular graft-versus-host disease (GVHD) and anterior uveitis following coronavirus disease 2019 (COVID-19) vaccination.

Case presentation

A 60-year-old man with primary myelofibrosis and GVHD after receiving allogeneic hematopoietic stem cell transplantation (HSCT), developed acute exacerbation of ocular GVHD and anterior uveitis after receiving first dose of COVID-19 vaccine. The patient developed erythema of the eyelids, conjunctival hyperemia, superficial punctate keratopathy, and prominent anterior chamber inflammation in both eyes. The ocular GVHD and anterior uveitis were managed with mainly topical corticosteroids, antibiotics, lubricants, and systemic corticosteroids, but were difficult to control. Intravitreal injection of dexamethasone was administered, and the inflammation gradually subsided 6 months after the onset of initial symptoms.

Conclusions

Clinicians should be aware of rare refractory anterior uveitis and acute exacerbation of ocular GVHD after COVID-19 vaccination in patients undergoing HSCT. Early diagnosis and aggressive treatment should be considered to reduce the likelihood of severe complications.
Novel compound heterozygous WDR35 variants in a Chinese patient associated with cranioectodermal dysplasia and ectopic testis: a case report and review of the literature
Authors: Li Lijie , Liu Cuihua , Tian Ming , Li Guangbo , Li Jitong
Published: August 2023

Background

WDR35 variants are known to cause a rare autosomal recessive disorder-Cranioectodermal dysplasia (CED). The CED patients are commonly present with facial dysmorphisms (frontal bossing and low-set ears), sagittal craniosynostosis, growth retardation, dolichocephaly, skeletal deformities (brachydactyly, terminal hypoplasia of the fingers and narrow thorax), ectodermal abnormalities (sparse hair, and finger/toe nail dysplasia), nephronophthisis, retinal dystrophy and hepatic fibrosis. Diagnosis of CED can be difficult because it presents with high genetic heterogeneity. However, our understanding of the phenotype of CED caused by WDR35 variants could be more explicit, and the correlation between genotype and phenotype needs further improvement.

Case presentation

We report a case of the first Chinses patient of CED caused by WDR35 variants, a 3-year-and-3-month-old patient, who was admitted to our hospital with frontal bossing, growth retardation, low set ears, dolichocephaly, sparse hair, and small limbs, abnormal renal function, and moderate anemia. The child showed a novel phenotype of the ectopic testis except for presenting typical CED characteristics, and he was identified with novel compound heterozygous WDR35 variants (c.2590 C > T, p.Gln864* and c.2408_2416del, p.Asn803_Ala805del; NM_001006657). He was given iron succinate and erythropoietin to improve anemia and to inhibit repeated metabolic acidosis and hyperkalemia through acid correction, diuretic, and potassium-lowering treatments. The parents refused to accept renal replacement therapy for their child and were discharged voluntarily.

Conclusions

This is the first reported case of the WDR35 variants that can lead to CED and ectopic testis, which is also the first Chinese patient associated with WDR35 variants. This study expands our understanding of genotype-phenotype association in patients with WDR35 variants and provides genetic counseling for prevention and intervention in this genetic disorder. Neonatal carriers should be followed up for kidney and CED-related diseases to detect warning signs.
An investigation of knowledge and attitudes towards antidepressants: a cross-sectional survey of Jordan’s six medical schools
Authors: Abdallat Mahmoud , Murshidi Rand , Taha Hana , Jaber Dunia Z. , Hammouri Muhammad , Al-Huneidy Leen , Aljayeh Maram , Ghanem Hadeel H. , Bedros Adees Wirtan , Al-Omairi Jaafar , Abbas Rand , Abu-usba Mustafa Ibrahim , Alkayed Zaid , Banimustafa Radwan , Al-Ani Abdallah
Published: August 2023

Objective

Depression is Jordan’s most ravaging mental illness. Despite the growth of antidepressant use, only a handful of studies examine the factors affecting antidepressant knowledge among healthcare workers or medical students. Therefore, we aimed to explore the knowledge and attitudes towards antidepressants across Jordan’s six medical schools.

Methods

Using a cross-sectional design, we investigated the knowledge and attitudes towards antidepressants through the Drug Attitude Inventory and a literature-validated knowledge domain. Clinical students from Jordan’s six medical schools were recruited. Differences in knowledge and attitudes scores were examined by year of study, medical school among other factors. A multivariate linear regression model was utilized to assess predictors of knowledge.

Results

We included a total of 1,234 participants representing Jordan’s six major schools of medicine. About 14.9% of participants had a personal history of antidepressant use while 20.5% reported family history of psychiatric disease. The majority of students demonstrated favorable attitudes towards antidepressants (74.1%). Students demonstrated an average understanding of antidepressants’ mechanism of action, side effects, but not indications in special populations. Senior medical students, higher GPA, higher family income, personal history of antidepressants, and family history of psychiatric illnesses were associated with significantly higher knowledge scores (all p-values < 0.001). In addition to attitudes scores, the aforementioned were positive predictors of knowledge scores in the multivariate model.

Conclusion

Medical students’ knowledge towards antidepressants leaves room for significant improvement. Yet, it is evident that significant differences for both attitudes and knowledge exist across medical schools which may indicate a gap in either training or teaching methodology.
Perceived impact of patients’ suicide and serious suicidal attempts on their treating psychiatrists and trainees: a national cross-sectional study in Saudi Arabia
Authors: Alshutwi Maha , Alawad Moayad , Alammari Mohammed , Almanea Mohannad , Alhumaid Rayan , Alkhalifah Azzam S. , Alosaimi Fahad D.
Published: August 2023

Background

Patient suicides are significant events that tremendously affect psychiatrists— personally and professionally. Very few studies have focused on studying the impact of both serious suicidal attempts and completed suicide on psychiatrists and psychiatry trainees.

Aim

This study assessed the prevalence and impact of patient suicide and serious suicidal attempts on psychiatrists and psychiatry trainees in Saudi Arabia.

Methods

This national cross-sectional study of psychiatrists and psychiatry trainees was conducted in Saudi Arabia. Participants completed an online self-administered questionnaire to assess emotional and professional impacts and the traumatic impact of patient suicide using the Impact of Event Scale-Revised (IES-R).

Results

178 psychiatrists were enrolled in this study. The prevalence rate of patient suicide among participants was 38.8%, and they experienced adverse emotional reactions. Additionally, among those who were not exposed to patient suicide, 12.9% reported exposure to serious suicide attempts, and almost all of them experienced related negative emotions. The most frequently reported emotions were sadness (61.95%), shock (48.91%), and guilt (25%), and these emotions lasted longer in completed patient suicide cases than attempted suicide. Nearly 84% of participants who experienced suicide reported its impact on their profession. The most reported professional impacts were increased focus on suicide cues, attention to legal aspects, and a tendency to hospitalize. Of participants who experienced suicide, 75.4% reported that the overall impact of suicidal events on their professional practice had improved. Of the total number of respondents who experienced either suicide or serious suicidal attempts, 10.9% reported symptoms of PTSD.

Conclusions

The study highlighted the emotional and professional burden that psychiatrists and psychiatry trainees experience due to patient’s completed suicides and serious suicidal attempts. Additionally, it emphasized the need for further research to study the benefits of implementing preparatory and training programs to help trainees and psychiatrists in such instances.