bluuebunny/crossref_metadata_2025 huggingface dataset:
COVID-19 and Vestibular Symptoms and Assessment: A Review
Authors: Aedo-Sánchez Cristian , Gutiérrez Gabriela , Aguilar-Vidal Enzo
Published: October 2023

Background: The current pandemic of COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in significant morbidity and mortality primarily associated with respiratory failure. However, it has also been reported that COVID-19 can evolve into a nervous system infection. The direct and indirect mechanisms of damage associated with SARS-CoV-2 neuropathogenesis could affect our sensory functionality, including hearing and balance. Summary: In order to investigate a possible association between SARS-CoV-2 viral infection and possible damage to the vestibular system, this review describes the main findings related to diagnosing and evaluating otoneurological pathologies. Key Messages: The clinical evidence shows that SARS-CoV-2 causes acute damage to the vestibular system that would not leave significant sequelae. Recovery is similar to vestibular pathologies such as vestibular neuronitis and benign paroxysmal positional vertigo. Further basic science, clinical, and translational research is needed to verify and understand the short- and long-term effects of COVID-19 on vestibular function.
Obinutuzumab-Induced Inflammatory Bowel Disease-Like Pancolitis: A First Case Report
Authors: Mendes Raquel R. , Figueiredo Pedro C. , Andrade Isabel
Published: October 2023

Introduction: Obinutuzumab is a type II anti-CD20 monoclonal antibody associated with a higher rate of toxicity when compared to rituximab. Gastrointestinal side-effects have been reported but data is still sparse. Case Presentation: A 47-year-old female with medical history of stage IV follicular non-Hodgkin lymphoma under chemotherapy presented with chronic bloody diarrhea and iron deficiency anemia. Endoscopic and histologic features resembled inflammatory bowel disease (IBD), imposing a thorough differential diagnosis. The diagnosis of obinutuzumab-induced pancolitis was made and the drug was suspended with subsequent clinical improvement. Conclusion: This is the first case report of obinutuzumab-induced pancolitis. The challenging differential diagnosis of IBD required a multidisciplinary approach with subsequent outcome and management implications.
Assessment of the Needs of Nephrology Divisions to Implement Return of Clinically Significant Research Genetic Results: A Survey of Nephrotic Syndrome Study Network (NEPTUNE) Investigators
Authors: Fishbein Jennifer E. , Wilson Dass Loryn , Lienczewski Chrysta , Kretzler Matthias , Gbadegesin Rasheed A. , Roberts J. Scott ,   NEPTUNE, Sampson Matthew G. , Uhlmann Wendy
Published: October 2023

Introduction: There is an increasing need to return genetic testing results to patients with kidney disease who were first genotyped on a research basis. Operationalizing this process in nephrology clinics is challenged by a limited number of genetic providers with whom to partner and a general lack of support services for all clinicians. Methods: We administered a survey in March 2022 to assess the current ability and ongoing needs of nephrology divisions to return clinically significant research genetic results to patients and to implement clinical genetic testing. This survey was distributed to institutions within the Nephrotic Syndrome Study Network (NEPTUNE) as part of the planning process for return of research genetic results to participants with pathogenic variants in Mendelian nephrotic syndrome genes. Results: Twenty-seven of 28 sites (96%) completed the survey. 59% (n = 16) of sites said they could handle return of research genetic results independently, with the rest expressing hesitation about the volume and complexity of patients and the limited resources and access to genetics services. 81% (n = 22) of these institutions did have a genetics clinic and 26% (n = 7) have a nephrology genetics clinic. However, 70% (n = 10) of these clinics have a waiting time over 1 month. 89% of divisions (n = 24) were conducting genetic testing and 96% of those (n = 23) used a kidney multi-gene panel. In 46% of divisions (n = 11), nephrologists were handling logistics of obtaining genetic testing samples themselves. Conclusion: We identified specific areas of support needed for return of clinically significant genetic results from research studies. While the surveyed nephrologists were conducting genetic testing, there were limitations in the support services available. This survey will help guide other research studies that wish to return genetic results to participants and also highlight the need for increasing support to effectively operationalize genetic testing in nephrology clinics.
Survival Benefit from Multimodal Treatment for Patients with Atypical Teratoid Rhabdoid Tumor in a Surveillance, Epidemiology, and End Results Database Analysis
Authors: Bhutada Abhishek S. , Adhikari Srijan , Cuoco Joshua A. , Rogers Cara M. , Marvin Eric A.
Published: October 2023

Introduction: Atypical teratoid rhabdoid tumor (ATRT) is among the most aggressive central nervous system malignancies. Although rare, this tumor typically afflicts young children and results in mortality within months. Here, we aim to determine key clinical features and treatment options that impact the survival of patients with ATRT. Methods: From the year 2000 to 2019, 363 patients with ATRT were identified from the Surveillance, Epidemiology, and End Results database. Univariate analysis was used to identify variables that had a significant impact on the primary endpoint of overall survival (OS). Multivariable analysis was then used to identify independent predictors of survival. Results: The median OS of the entire cohort was 13 months. Univariate analysis identified ages between 1 and 3 years, ages between 4 and 17 years, years of diagnosis between 2010 and 2019, and the receipt of treatment to have a significant impact on survival. In multivariable analysis, ages between 1 and 3 years and receipt of treatment were the only significant independent predictors of survival. The median OS was significantly greater in patients who received surgical treatment, chemotherapy, or radiation when compared to those who did not receive any treatment. In general, the receipt of any combination of therapies improved the median OS significantly. The receipt of triple therapy had the greatest impact on survival. Discussion: This study highlights the survival benefit of a multimodal approach in the treatment of ATRT. The use of triple therapy, including surgery, radiation, and chemotherapy, was found to have the greatest survival benefit for patients. Overall, these findings may guide future care for patients with ATRT.
Renal Outcomes in Older Adults with Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis: A New Prediction Model
Authors: Zhang Shuo , Chen Xin , Hou Zuoxian , Xia Peng , Shi Xiaoxiao , Wu Haiting , Wen Yubing , Qin Yan , Tian Xinping , Chen Limeng
Published: October 2023

Introduction: Older patients with antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV) commonly experience renal impairment and poor prognoses. This study aimed to establish a risk-scoring system for predicting composite renal outcomes in older patients with AAV. Methods: This retrospective observational study included all patients with AAV hospitalized in a single-center tertiary hospital in China between January 2013 and April 2022. Patients aged ≥65 years were defined as older adults and short-term composite renal outcomes included a ≥25% reduction in estimated glomerular filtration rate (eGFR) (for AKI), renal replacement therapy, provision of renal replacement therapy (long-term dialysis, kidney transplant, or sustained eGFR <15 mL/min/1.73 m), or all-cause mortality. Patients were randomly divided into development and validation cohorts (2:1). Logistic regression analysis was performed in the development cohort to analyze risk factors. The scoring system was established accordingly and further validated in the validation cohort. Results: 1,203 patients were enrolled in the study, among whom the older adult group accounted for 36% with a mean age of 71. The older adult group had a worse prognosis, a higher mortality rate, a higher rate of end-stage renal disease, and worsening renal function. Logistic regression showed that age >75 years, chronic heart disease, and elevated serum creatinine and D-dimer values were risk factors for poor prognosis in patients with AAV. The development and validation cohorts in patients with AAV produced area under the curve values of 0.82 (0.78–0.86) and 0.83 (0.77–0.89), respectively. Conclusion: We established a risk-scoring system based on baseline clinical characteristics to predict composite renal outcomes in patients with AAV. Our results suggest that more attention should be paid to older patients with severe renal impairment and active inflammation.
Anti-Vascular Endothelial Growth Factor Therapy Regimens for Polypoidal Choroidal Vasculopathy: A Systematic Review
Authors: Mihalache Andrew , Hatamnejad Amin , Patil Nikhil S. , Popovic Marko M. , Muni Rajeev H. , Kertes Peter J. , Wong David T.
Published: October 2023

Introduction: There are no guidelines on the optimal anti-vascular endothelial growth factor (anti-VEGF) monotherapy regimen for patients with polypoidal choroidal vasculopathy (PCV). In this study, we aimed to assess the comparative safety and efficacy of different treatment regimens of anti-VEGF monotherapy for PCV. Methods: We conducted a systematic literature search on Ovid MEDLINE, Embase, and Cochrane Library from January 2000 to May 2023 for comparative articles reporting on different treatment regimens of anti-VEGF agents in PCV. Our primary outcomes were the final best-corrected visual acuity (BCVA) and the change in BCVA from baseline. Secondary outcomes were the final retinal thickness (RT), the change in RT from baseline, the rate of polyp closure, and the incidence of adverse events. Results: A total of 10,440 studies were screened, and seven studies reporting on 636 eyes with PCV at baseline were included in this systematic review. One RCT of 53 eyes found a similar final BCVA, change in BCVA from baseline, final RT, and complete polyp closure rate between a treat-and-extend (T&E) regimen and a bimonthly fixed-dosing regimen of aflibercept. This trial also found superiority of T&E for change in RT from baseline. One observational study of 33 eyes found a similar BCVA at last study observation between a pro re nata (PRN) regimen and bimonthly fixed-dosing regimen of aflibercept. One observational study of 42 eyes found a similar change in BCVA from baseline and complete polyp closure rate between a PRN regimen and bimonthly fixed-dosing regimen of aflibercept. One RCT of 249 eyes found a similar change in BCVA and RT from baseline, as well as polyp closure, between a T&E regimen and fixed 12-week dosing regimen of conbercept. One observational study of 30 eyes found a superiority of T&E aflibercept for change in BCVA and risk of polyp recurrence, compared to a PRN regimen. Conclusion: Overall, there is a paucity of evidence comparing various treatment regimens of anti-VEGF therapy in patients with PCV. This limited evidence suggests that current treatment regimens are similarly efficacious, though T&E aflibercept achieved superior outcomes when compared to bimonthly dosing or PRN in some individual studies. Further trials are needed to confirm or refute these findings.
Altered Intestinal Microbial Flora and Metabolism in Patients with Idiopathic Membranous Nephropathy
Authors: Shi Xiaohu , Li Zhaojun , Lin Weifeng , Shi Wenying , Hu Rongrong , Chen Gang , Li Xuemei , Li Xuewang , Zhang Sen
Published: October 2023

Introduction: Dysbiosis of the intestinal microbiome and related metabolites have been observed in chronic kidney disease, yet their roles in idiopathic membranous nephropathy (IMN) are poorly understood. Methods: In this study, we describe the variation of intestinal bacteria and fecal metabolites in patients with IMN in Chinese population. Stool samples were collected from 41 IMN patients at the beginning of diagnosis confirmation and 41 gender- and age-matched healthy control (HC). Microbial communities are investigated by sequencing of 16S rRNA genes and functional profiles predicted using Tax4Fun, and the correlation between intestinal bacteria and IMN clinical characteristics is also analyzed. Untargeted metabolomic analysis is performed to explore the relationship between colon’s microbiota and fecal metabolites. Results: IMN gastrointestinal microbiota demonstrates lower richness and diversity compared to HC, and exhibits a marked taxonomic and inferred functional dysbiosis when compared to HC. Some genera are closely related to the clinical parameters, such as Citrobacter and Akkermansia. Twenty characteristic microbial biomarkers are selected to establish a disease prediction model with a diagnostic accuracy of 93.53%. Fecal metabolomics shows that tryptophan metabolism is reduced in IMN patients but uremic toxin accumulation in feces is not noticeable. Fecal microbiota transplantation demonstrates that gut dysbiosis impairs gut permeability in microbiota-depleted mice and induces NOD-like receptor activation in the kidneys. Conclusions: Clarifying the changes in intestinal microbiota in IMN patients will help further know the pathogenesis of this disease, and microbiota-targeted biomarkers will provide a potentially powerful tool for diagnosing and treating IMN.
Taurine Supplementation for 48-Months Improved Glucose Tolerance and Changed ATP-Related Enzymes in Avians
Authors: Neuwirth Lorenz S. , Gökhan Nurper , Kaye Sarrah , Meehan Edward F.
Published: October 2023

Avians differ from mammals, especially in brain architecture and metabolism. Taurine, an amino acid basic to metabolism and bioenergetics, has been shown to have remarkable effects on metabolic syndrome and ameliorating oxidative stress reactions across species. However, less is known regarding these metabolic relationships in the avian model. The present study serves as a preliminary report that examined how taurine might affect avian metabolism in an aged model system. Two groups of pigeons (Columba livia) of mixed sex, a control group and a group that received 48 months of taurine supplementation (0.05% w/v) in their drinking water, were compared by using blood panels drawn from their basilic vein by a licensed veterinarian. From the blood panel data, taurine treatment generated higher levels of three ATP-related enzymes: glutamate dehydrogenase (GLDH), lactate dehydrogenase (LDH), and creatine kinase (CK). In this preliminary study, the role that taurine treatment might play in the adult aged pigeon’s metabolism on conserved traits such as augmenting insulin production as well as non-conserved traits maintaining high levels of ATP-related enzymes was examined. It was found that taurine treatment influenced the avian glucose metabolism similar to mammals but differentially effected avian ATP-related enzymes in a unique way (i.e., ∼×2 increase in CK and LDH with a nearly ×4 increase in GLDH). Notably, long-term supplementation with taurine had no negative effect on parameters of lipid and protein metabolism nor liver enzymes. The preliminary study suggests that avians may serve as a unique model system for investigating taurine metabolism across aging with long-term health implications (e.g., hyperinsulinemia). However, the suitability of using the model would require researchers to tightly control for age, sex, dietary intake, and exercise conditions as laboratory-housed avian present with very different metabolic panels than free-flight avians, and their metabolic profile may not correlate one-to-one with mammalian data.
MiR-320a Acts as a Tumor Suppressor in Somatotroph Pituitary Neuroendocrine Tumors by Targeting BCAT1
Authors: Zhao Sida , Li Bin , Gao Hua , Zhang Yazhuo
Published: October 2023

Introduction: Aberrant miR-320a has been reported to be involved in the tumorigenesis of several cancers. In our previous study, we identified the low expression of circulating miR-320a in patients with somatotroph pituitary neuroendocrine tumor (PitNET); however, the role of miR-320a in somatotroph PitNET proliferation is still unclear. Methods: Cell viability and colony formation assays were used to detect the effect of miR-320a and BCAT1 on GH3 cells. TargetScan was used to identify the target genes of miR-320a. Dual-luciferase reporter gene assay was used to explore the relation between miR-320a and BCAT1. Transcriptome and proteome analyses were performed between somatotroph PitNETs and healthy controls. The expression level of miR-320a in somatotroph PitNETs were detected by RT-qPCR and Western blot. Results: miR-320a mimics inhibit cell proliferation, while miR-320a inhibitors promote cell proliferation in GH3 cells. An overlap analysis using a Venn diagram revealed that BCAT1 is the only target gene of miR-320a overexpressed in somatotroph PitNETs compared to healthy controls, as revealed by both microarray and proteomics results. A dual-luciferase reporter gene assay showed that miR-320a may bind to the BCAT1-3′UTR. The transfection of miR-320a mimics downregulated the expression and miR-320a inhibitors and upregulated the expression of BCAT1 in GH3 cells. The interference of BCAT1 expression in GH3 cells downregulated cell proliferation and growth. Pan-cancer analyses demonstrated that high BCAT1 expression often indicates a poor prognosis. Conclusion: Our findings illustrate that miR-320a may function as a tumor suppressor and BCAT1 may promote tumor progression. miR-320a may inhibit the growth of somatotroph PitNETs by targeting BCAT1.
Practical Guideline for Prevention of Patchy Hair Loss following CyberKnife Stereotactic Radiosurgery for Calvarial or Scalp Tumors: Retrospective Analysis of a Single Institution Experience
Authors: Park David J. , Marianayagam Neelan J. , Yener Ulas , Tayag Armine , Ustrzynski Louisa , Emrich Sara C. , Pollom Erqi , Soltys Scott , Meola Antonio , Chang Steven D.
Published: October 2023

Introduction: Patchy alopecia is a common adverse effect of stereotactic radiosurgery (SRS) on the calvarium and/or scalp, yet no guidelines exist for its prevention. This study aims to investigate the incidence and outcomes of patchy alopecia following SRS for patients with calvarial or scalp lesions and establish preventive guidelines. Methods: The study included 20 patients who underwent CyberKnife SRS for calvarial or scalp lesions, resulting in a total of 30 treated lesions. SRS was administered as a single fraction for 8 lesions and hypofractionated for 22 lesions. The median SRS target volume was 9.85 cc (range: 0.81–110.7 cc), and the median prescription dose was 27 Gy (range: 16–40 Gy), delivered in 1–5 fractions (median: 3). The median follow-up was 15 months. Results: Among the 30 treated lesions, 11 led to patchy alopecia, while 19 did not. All cases of alopecia resolved within 12 months, and no patients experienced other adverse radiation effects. Lesions resulting in alopecia exhibited significantly higher biologically effective dose (BED) and single-fraction equivalent dose (SFED) on the overlying scalp compared to those without alopecia. Patients with BED and SFED exceeding 60 Gy and 20 Gy, respectively, were 9.3 times more likely to experience patchy alopecia than those with lower doses. The 1-year local tumor control rate for the treated lesions was 93.3%. Chemotherapy was administered for 26 lesions, with 11 lesions receiving radiosensitizing agents. However, no statistically significant difference was found. Conclusion: In summary, SRS is a safe and effective treatment for patients with calvarial/scalp masses regarding patchy alopecia near the treated area. Limiting the BED under 60 Gy and SFED under 20 Gy for the overlying scalp can help prevent patchy alopecia during SRS treatment of the calvarial/scalp mass. Clinicians can use this information to inform patients about the risk of alopecia and the contributing factors.
Complete Response on Larotrectinib in NTRK2 Fusion-Positive Non-Small Cell Lung Cancer
Authors: Frehner Lorenz , Haefliger Simon , Cerciello Ferdinando , Grob Tobias , Schmid Sabine
Published: October 2023

In patients with non-small cell lung cancer (NSCLC) harboring a fusion of the neurotrophic receptor kinase (NTRK) gene 1 or 3, treatment with tropomyosin kinase (TRK) inhibitors have shown promising results, however so far no data on efficacy of these agents in patients with NSCLC and NTRK2 fusion are available. We present a case of a female patient with NTRK2-positive NSCLC with a complete ongoing response on therapy with larotrectinib, suggesting efficacy of first-generation TRK inhibitors also in NTRK2-positive NSCLC.
Use of Hydroxychloroquine in Hair Disorders
Authors: Ravipati Advaitaa , Randolph Michael , Al-Salhi Waleed , Tosti Antonella
Published: October 2023

Hydroxychloroquine (HCQ) is an antimalarial that is utilized to treat a range of dermatologic and autoimmune disorders. With its ability to alter immunologic mechanisms, it has been used to slow or halt the progression of hair loss in conditions secondary to autoimmune dysfunction. Lichen planopilaris (LPP), frontal fibrosing alopecia (FFA), and alopecia areata (AA) are hair disorders with underlying autoimmune components and no standardized treatment guidelines. We summarized the available literature on the use of HCQ to treat LPP, FFA, and AA. For all three conditions, HCQ showed variable efficacy from halted hair loss to no improvement. While patients did show success with HCQ treatment, there were no clear treatment patterns. Regimens ranged from HCQ monotherapy to combination treatments with other agents like steroids. Overall, HCQ should certainly be considered by clinicians as a treatment option for patient suffering from these hair disorders. While there is no standardized treatment, incorporation of HCQ should take into consideration individual patient characteristics, clinical judgment, and risks of side effects.
Bariatric Surgeries, from Weight Loss to Weight Regain: A Retrospective Five-Years Cohort Study
Authors: Hatami Mahsa , Pazouki Abdolreza , Hosseini-baharanchi Fatemeh Sadat , Kabir Ali
Published: October 2023

Introduction: Bariatric surgery may lead to unsatisfactory weight loss, weight loss plateau, and even weight regain after various types of surgery. Despite the numerous studies, the mid-term results of surgery, after repetitive weight fluctuations remain a major concern. The aim of the present study was to determine the key time points of weight changes after three types of bariatric procedures, as well as to determine 5-year weight loss outcome after surgery. Methods: This is a retrospective cohort study including patients with morbid obesity conducted in the Minimally Invasive Surgery Research Center. The patients underwent one of the three types of bariatric surgeries including laparoscopic sleeve gastrectomy (LSG), Roux-en-Y gastric bypass (RYGB), and one-anastomosis gastric bypass (OAGB), who had been followed up for weight loss trend during 5 years postoperatively. Results: The mean excessive weight loss (%EWL) and total weight loss (%TWL) of 2,567 participants with obesity (mean age = 39.03, mean BMI = 45.67) in the first 6 months after surgery was independent of the type of surgery (p > 0.05). OAGB and RYGB showed significantly higher weight loss compared to LSG in ninth and 24th month after surgery, respectively (p < 0.05). The 5 years %WL could be comparable with %WL in 6, 9, and 12 months after LSG, RYGB, and OAGB, respectively. Conclusion: OAGB provides the fastest and highest %EWL and %TWL, while LSG induced the earliest and largest weight plateau and weight regain during 5-years post-surgery. The pattern of early weight loss could predict the mid-term outcome of bariatric surgery. So, early identification of suboptimal weight loss could enhance long-term weight loss.
Association of Epidermal Biophysical Properties with Obesity and Its Implications
Authors: Zhu Tingting , Yang Shuyun , Mauro Theodora M. , Man Mao-Qiang
Published: October 2023

Background: Obesity is a condition defined by an excess amount of body fat, with body mass index (BMI) of 30 and higher. It is associated with a number of other medical conditions, including insulin resistance, diabetes mellitus, and cardiovascular diseases, as well as dyslipidemia, and it is also associated with several cutaneous disorders such as atopic dermatitis, psoriasis, intertriginous dermatitis, acanthosis nigricans and skin infections. Summary: Evidence suggests a link between obesity and epidermal dysfunction. Generally, individuals with obesity display higher transepidermal water loss rate and lower stratum corneum hydration levels, although no association of obesity with epidermal dysfunction has been documented. Results of skin surface pH are controversial. But study demonstrated a positive correlation of BMI with skin surface pH on both the forearm and the shin in males, suggesting that the changes in epidermal function vary with gender in individuals with obesity. Key Messages: This review summarizes the association between obesity and epidermal function, and discusses possible underlying mechanisms. Individuals with obesity exhibit poor epidermal permeability barrier and lower stratum corneum hydration levels. Because of the pathogenic role of compromised epidermal function in inflammation, which is also linked to obesity, improvement in epidermal function could benefit individuals with obesity, particularly those with abnormalities in epidermal function.
MRI Using Gadoxetic Acid in the Work-Up of Liver Nodules Not Conclusively Benign in Budd-Chiari Syndrome: A Prospective Long-Term Follow-Up
Authors: García-Criado Angeles , Rimola Jordi , Seijo Susana , Darnell Anna , Belmonte Ernest , Sapena Victor , Moreno-Rojas Julián , Pérez Valeria , Hernández-Gea Virginia , Ayuso Carmen , Reig Maria , García-Pagán Juan Carlos , Bruix Jordi
Published: October 2023

Introduction: The incidence of hepatocellular carcinoma (HCC) in Budd-Chiari syndrome (BCS) is unknown and there is no validated diagnostic work-up to define the liver nodules with arterial phase hyperenhancement (APHE), suggesting malignancy. This prospective study evaluates HCC incidence in a Western cohort of patients with BCS and assesses the performance of MRI with hepatobiliary contrast (HB-MRI) for nodule characterization. Methods: Patients with BCS followed in our hospital were prospectively evaluated by MRI with extracellular contrast (EC-MRI). Nodules with APHE categorized as non-conclusively benign by 2 radiologists were studied by HB-MRI and reviewed by 2 radiologists blinded to the EC-MRI results. A new EC-MRI 1 year later and clinical, analytical, and sonographic follow-up every 6 months for a median of 10 years was performed. Results: A total of 55 non-conclusively benign nodules with APHE were detected at EC-MRI in 41 patients. While 32 of them were suggestive of HCC by EC-MRI, all the 55 nodules showed increased uptake of hepatobiliary contrast. An unequivocal central scar was seen in 12/55 nodules at HB-MRI regardless of it was not detected on the EC-MRI. None of the nodules was hypointense in the hepatobiliary phase (HBP). HCC was not detected during a median of 10 years of follow-up. Conclusions: Detection of nodules with APHE is frequent in patients with BCS, but HCC is rare in Western patients with BCS. While EC-MRI may detect nodules suggesting malignancy, the identification of contrast uptake in the HBP at HB-MRI may help categorize them as benign.
Chronic Lymphocytic Leukemia: Disease Biology
Authors: Koehrer Stefan , Burger Jan A.
Published: October 2023

Background: B-cell receptor (BCR) signaling is crucial for normal B-cell development and adaptive immunity. In chronic lymphocytic leukemia (CLL), the malignant B cells display many features of normal mature B lymphocytes, including the expression of functional B-cell receptors (BCRs). Cross talk between CLL cells and the microenvironment in secondary lymphatic organs results in BCR signaling and BCR-driven proliferation of the CLL cells. This critical pathomechanism can be targeted by blocking BCR-related kinases (BTK, PI3K, spleen tyrosine kinase) using small-molecule inhibitors. Among these targets, Bruton tyrosine kinase (BTK) inhibitors have the highest therapeutic efficacy; they effectively block leukemia cell proliferation and generally induce durable remissions in CLL patients, even in patients with high-risk disease. By disrupting tissue homing receptor (i.e., chemokine receptor and adhesion molecule) signaling, these kinase inhibitors also mobilize CLL cells from the lymphatic tissues into the peripheral blood (PB), causing a transient redistribution lymphocytosis, thereby depriving CLL cells from nurturing factors within the tissue niches. Summary: The clinical success of the BTK inhibitors in CLL underscores the central importance of the BCR in CLL pathogenesis. Here, we review CLL pathogenesis with a focus on the role of the BCR and other microenvironment cues. Key Messages: (i) CLL cells rely on signals from their microenvironment for proliferation and survival. (ii) These signals are mediated by the BCR as well as chemokine and integrin receptors and their respective ligands. (iii) Targeting the CLL/microenvironment interaction with small-molecule inhibitors provides a highly effective treatment strategy, even in high-risk patients.
The Healthy Ageing Questionnaire Index: Validation in the Singapore Longitudinal Ageing Study
Authors: Ng Tze Pin , Gwee Xinyi , Chua Denise Q.L. , Wee Shiou Liang , Cheong Chin Yee , Yap Philip Lin Kiat , Yap Keng Bee
Published: October 2023

Introduction: Healthy ageing (HA) indices typically use full questionnaire, performance- or blood-based assessment of functional ability which are time-consuming and resource-intensive. We developed and validated a simple and brief Healthy Ageing Questionnaire (HAQ) index with comparable measurement accuracy. Methods: The 15-item HAQ (scored 0–100) was developed using data of 500 participants in the Singapore Study of Successful Ageing (SSOSA), a sub-cohort of the Singapore Longitudinal Ageing Study (SLAS-2). Its construct, concurrent, and predictive validity were evaluated in 2,161 participants in the SLAS-2 who were non-participants of the SSOSA. Results: The HAQ index (mean = 64.0, SD = 11.8) showed a coherent 3-factor structure (Cronbach’s alpha = 0.735). HAQ scores were higher among participants who were female, highly educated, not living alone, non-smoking, non-alcohol drinkers, not at risk of malnutrition, were robust or pre-frail, not disabled, had no or <5 medical conditions, and no recent fall or hospitalization. It was positively correlated with Mini-Mental State Examination and life satisfaction, and negatively correlated with age, logMAR vision, 5 times sit-and-stand, and timed-up-and-go. The HAQ index was significantly correlated but showed modest concordance with the Rowe-Kahn SA index. Increasing HAQ index quintiles were associated with decreased mortality risks from 40.6 to 9.7 deaths per 1,000 person-years; covariate-adjusted hazard ratio for the highest Q5 levels (HAQ score >70) was 0.44 (95% CI = 0.28–0.67). Using receiver operating characteristics analysis of predictive accuracy for survival, the area under the curve of HAQ was 0.675, and Rowe-Kahn SA index was 0.660 (p = 0.361). Conclusion: The HAQ is a brief and accurate HA index that is potentially useful across diverse settings and purposes in research, healthcare, and policy-making.
Momordica charantia Enhances Tendon Healing in Rats: An Experimental Study
Authors: Erdoğan Furkan , Kaplan Arife Ahsen , Coşkun Hüseyin Sina , Altun Gamze , Altunkaynak Berrin Zuhal , Kelsaka Ebru , Kaplan Suleyman , Pişkin Ahmet
Published: October 2023

Momordica charantia (MC) is a traditional plant widely used since ancient times for wound healing. This study evaluated its potential effects on tendon healing. Adult male Wistar albino rats (n = 32, 8 rats in each group) were anesthetized, and their Achilles tendons were prepared for surgical procedures. Group 1 (Cont = control group) was not subjected to any surgery and was used as a control group for baseline values. Group 2 (PR = primary repair group) underwent primary repair (PR) with a monofilament suture after a full-thickness incision of the Achilles tendon. A full-thickness incision was also made to the Achilles tendon of group 3 (CT = collagen tube-administered group), followed by PR and collagen tube insertion. In group 4 (MC = M. charantia-administered group), 1 mL of MC extract was applied locally on the collagen tube in addition to the surgical procedure applied to group 3. The Achilles tendons were excised on the postoperative 40th day and examined stereologically, histologically, and bioinformatically. Data showed that the total volume of the collagen fibers was higher in MC and CT groups than in the PR group. The total volume of the tendon was decreased in MC and CT groups than in the Cont group. The ratios between the volumes of the collagen fibers and total tendon in the MC and CT groups were significantly different from PR, but not different from the Cont group. Additionally, MC improved tenoblastic activity, collagen production, and neovascularization. Bioinformatic interactions showed that the proteases of MC could trigger the signals playing a role on vasculogenesis, reducing inflammation, and contributing to tenoblast activation and collagen remodeling. MC extract ameliorates the healing of injured tendon and can provide satisfactory tendon repair. Further works are recommended to explore the healing capacity of MC.
Placental Histologic Abnormalities and 2-Year Outcomes in Neonatal Hypoxic-Ischemic Encephalopathy
Authors: Gonzalez Fernando F. , Voldal Emily , Comstock Bryan A. , Mayock Dennis E. , Goodman Amy M. , Cornet Marie-Coralie , Wu Tai-Wei , Redline Raymond W. , Heagerty Patrick , Juul Sandra E. , Wu Yvonne W.
Published: October 2023

Objective: We aimed to examine the association between placental abnormalities and neurodevelopmental outcomes in a multicenter cohort of newborn infants with hypoxic-ischemic encephalopathy (HIE) that underwent therapeutic hypothermia. We hypothesized that subjects with acute placental abnormalities would have reduced risk of death or neurodevelopmental impairment (NDI) at 2 years of age after undergoing therapeutic hypothermia compared to subjects without acute placental changes. Study Design: Among 500 subjects born at ≥36 weeks gestation with moderate or severe HIE enrolled in the High-dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial, a placental pathologist blinded to clinical information reviewed clinical pathology reports to determine the presence of acute only, chronic only, or both acute and chronic histologic abnormalities. We calculated adjusted relative risks (aRRs) for associations between placental pathologic abnormalities and death or NDI at age 2 years, adjusting for HIE severity, treatment assignment, and site. Result: 321/500 subjects (64%) had available placental pathology reports. Placental abnormalities were characterized as acute only (20%), chronic only (21%), both acute and chronic (43%), and none (15%). The risk of death or NDI was not statistically different between subjects with and without an acute placental abnormality (46 vs. 53%, aRR 1.1, 95% confidence interval (CI): 0.9, 1.4). Subjects with two or more chronic lesions were more likely to have an adverse outcome than subjects with no chronic abnormalities, though this did not reach statistical significance (55 vs. 45%, aRR 1.24, 95% CI: 0.99, 1.56). Conclusion: Placental pathologic findings were not independently associated with risk of death or NDI in subjects with HIE. The relationship between multiple chronic placental lesions and HIE outcomes deserves further study.
Liver Enzymes and the Risk of Stroke among the General Japanese Population: A Prospective Cohort Study
Authors: Arafa Ahmed , Kokubo Yoshihiro , Kashima Rena , Matsumoto Chisa , Koga Masatoshi
Published: October 2023

Introduction: Stroke is a major cause of morbidity and mortality. Liver enzymes, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transpeptidase (GGT), are markers of liver diseases with potential cardiovascular implications. This study aimed to investigate the prospective association between liver enzymes and stroke risk. Methods: We analyzed data from 3,379 men and 4,007 women without cardiovascular disease and registered in the Suita Study, a Japanese population-based prospective cohort study. The hazard ratios (HRs) and 95% confidence intervals (95% CIs) of stroke risk were estimated per quintiles of ALT, AST, and GGT in men and women. Results: Within a median follow-up period of 16.7 years, 438 incident stroke events were diagnosed. In men, compared to the second quintiles, the fifth (highest) quintiles of liver enzymes showed increased stroke risks: HRs (95% CIs) = 2.07 (1.35, 3.18) in ALT, 1.66 (1.10, 2.53) in AST, and 1.76 (1.11, 2.81) in GGT. The associations did not change with cerebral infarction risk: HRs (95% CIs) = 2.09 (1.24, 3.50) in ALT, 1.84 (1.11, 3.06) in AST, and 1.74 (1.00, 3.04) in GGT. The lowest ALT, AST, and GGT quintiles tended to show increased stroke and cerebral infarction risks, yet these associations were statistically insignificant. No such associations were shown in women. Conclusion: Elevated ALT, AST, and GGT levels were associated with increased stroke and cerebral infarction risks among Japanese men.
Alleviation of Oxidative Stress during Hemodialysis Sessions by Hemodialysis Membrane Innovation: A Multidisciplinary Perspective
Authors: Li Yupei , Luo Xinyao , Yang Mei , Su Baihai
Published: October 2023

Oxidative stress is prevalent in end-stage kidney disease patients receiving chronic hemodialysis and is associated with heavy cardiovascular disease burdens and increased mortality risks. Hemoincompatible hemodialysis membranes per se contribute to the activation of oxidative reactions and the generation of oxygen free radicals. Since the early 1990s, vitamin E-coated membranes have been extensively used in hemodialysis patients to reduce oxidative stress during hemodialysis sessions. However, the beneficial effects of vitamin E-coated membranes versus unmodified synthetic membranes on long-term patient-centered outcomes, such as survival, quality of life, and prevalence of cardiovascular diseases, remain controversial. Accordingly, novel antioxidant hemodialysis membranes were prepared to replace the use of vitamin E-coated membranes despite the translational research on these membranes unfortunately coming to a standstill. In this review, we first summarize the state-of-the-art on the use of vitamin E-coated membranes in hemodialysis patients to highlight their strengths and limitations. Then, we discuss the latest advances in fabricating antioxidant hemodialysis membranes and provide perspectives to bridge knowledge gaps between laboratorial investigations and clinical practice in fabricating antioxidant hemodialysis membranes.
Spontaneous Remission in a Patient with Chronic Myeloid Leukemia: A Case Report
Authors: Alshurafa Awni , Ekeibed Yeslem , Akiki Susanna , Alzeyara Muna , Nawaz Zafar , Yassin Mohamed A.
Published: October 2023

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm in which granulocytic cells are the main proliferative component. At diagnosis, more than 90% of CML cases have the characteristic Philadelphia chromosome, containing the BCR::ABL1 fusion gene. The natural history of untreated CML is an initial indolent chronic phase which will be followed by an accelerated phase, blast phase, or both. Tyrosine kinase inhibitors (TKIs) have dramatically altered the natural history of CML. TKI discontinuation with the goal of treatment-free remission is currently part of current management recommendations. However, spontaneous remission without receiving any treatment is extraordinarily rare in CML patients. Herein, we report a 56-year-old male who presented with leukocytosis and was diagnosed as a case of CML in the chronic phase; however, treatment with TKIs was not initiated due to spontaneous hematological as well as molecular remission.
Simple Scoring System for Esophagogastric Varices Prediction in Hepatocellular Carcinoma Patients without Liver Stiffness Evaluation
Authors: Hiraoka Atsushi , Tada Fujimasa , Ohama Hideko , Fukumoto Mai , Matsuoka Kana , Matsuda Takuya , Nakatani Kosuke , Yanagihara Emi , Saneto Hironobu , Izumoto Hirofumi , Murakami Taisei , Onishi Kei , Kitahata Shogo , Kanemitsu-Okada Kozue , Kawamura Tomoe , Kuroda Taira , Miyata Hideki , Tsubouchi Eiji , Hirooka Masashi , Abe Masanori , Matsuura Bunzo , Ninomiya Tomoyuki , Hiasa Yoichi
Published: October 2023

Introduction: For predicting esophagogastric varices (EGVs), the Virtual Baveno VII Consensus Workshop has proposed a combination of liver stiffness determination and platelet count measurement using a FibroScan®. However, FibroScan® is not available at all institutions. The present study aimed to develop a simple method to predict development of EGV using only general blood examination results. Materials and Methods: A total of 1,090 hepatocellular carcinoma patients were enrolled, after excluding 956 with major portal vein tumor thrombus (Vp3/Vp4) or without upper gastrointestinal endoscopy examination results available. Those with EGV (≥ grade F2) or a history of treatment for the condition were defined as positive for significant EGV, and then clinical factors were retrospectively evaluated to determine indicators of occurrence. Results: Logistic multivariate analysis showed platelet count (≤12 × 104/μL) (odds ratio [OR] 3.79, p < 0.001), mALBI grade 2a (OR 1.52, p = 0.036), and mALBI 2b or 3 (OR 3.46, p < 0.001) as significant predictive factors. Based on the OR values, platelet count (≤12 × 104/μL) and mALBI grade 2b/3 were each assigned 2 points and mALBI 2a was given 1 point, with the result termed recommendation for EGV screening (REGS) score. Significant EGV occurrence was noted in 2.9% (9/311) of the patients with a REGS score 0, 11.0% (13/118) with a score 1, 19.3% (53/274) with a score 2, 29.5% (39/132) with a score 3, and 38.0% (97/255) with a score 4 (p < 0.001). Conclusion: The findings indicate that REGS score can provide useful predictive information for development of significant EGV without the need for special equipment such as a FibroScan®.
Distinct Biomarkers of ANT Stimulation and Seizure Freedom in an Epilepsy Patient with Ambulatory Hippocampal Electrocorticography
Authors: Skelton Henry M. , Brandman David M. , Bullinger Katie , Isbaine Faical , Gross Robert E.
Published: October 2023

Introduction: Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) and responsive neurostimulation (RNS) of the hippocampus are the predominant approaches to brain stimulation for treating mesial temporal lobe epilepsy (MTLE). Both are similarly effective at reducing seizures in drug-resistant patients, but the underlying mechanisms are poorly understood. In rare cases where it is clinically indicated to use RNS and DBS simultaneously, ambulatory electrophysiology from RNS may provide the opportunity to measure the effects of ANT DBS in the putative seizure onset zone and identify biomarkers associated with clinical improvement. Here, one such patient became seizure free, allowing us to identify and compare the changes in hippocampal electrophysiology associated with ANT stimulation and seizure freedom. Methods: Ambulatory electrocorticography and clinical history were retrospectively analyzed for a patient treated with RNS and DBS for MTLE. DBS artifacts were used to identify ANT stimulation periods on RNS recordings and measure peri-stimulus electrographic changes. Clinical history was used to determine the chronic electrographic changes associated with seizure freedom. Results: ANT stimulation acutely suppressed hippocampal gamma (25–90Hz) power, with minimal theta (4–8Hz) suppression and without clear effects on seizure frequency. Eventually, the patient became seizure free alongside the emergence of chronic gamma increase and theta suppression, which started at the same time as clobazam was introduced. Both seizure freedom and the associated electrophysiology persisted after inadvertent DBS discontinuation, further implicating the clobazam relationship. Unexpectedly, RNS detections and long episodes increased, although they were not considered to be electrographic seizures, and the patient remained clinically seizure free. Conclusion: ANT stimulation and seizure freedom were associated with distinct, dissimilar spectral changes in RNS-derived electrophysiology. The time course of these changes supported a new medication as the most likely cause of clinical improvement. Broadly, this work showcases the use of RNS recordings to interpret the effects of multimodal therapy. Specifically, it lends additional credence to hippocampal theta suppression as a biomarker previously associated with seizure reduction in RNS patients.
Neonatal Research at the Archiospedale Santo Spirito in Rome
Authors: Obladen Michael
Published: October 2023

Abandoning infants was a heritage of the Roman Empire. Foundling hospitals were established in Italy earlier and in greater number than in other countries; their goal was to prevent infanticides. The Foundling Hospital in Rome, established in the Santo Spirito Church in 1204, paved the way toward modern hospital care and child protection. The Order of the Holy Spirit was appointed by Pope Innocent III to care for foundlings, and set up a network of infant nurseries all over Europe. Poor unmarried pregnant women received obstetric services free of charge. Infants were admitted anonymously by the ruota, a baby hatch or turning wheel. The Order’s rule regulated infants’ admission, care, nutrition by wet nurses, and boarding out to foster families in the countryside. Chief physicians of the Santo Spirito Hospital were often Sapienza University professors and/or personal physicians to the Popes. Among them were Realdo Colombo, Andrea Caesalpino, Giovanni Lancisi, Giuseppe Flajani, Domenico Morichini, and Tommaso Prelà. They made major scientific progress in anatomy and surgery: descriptions of the pulmonary blood transit, embryonic formation, fetal circulation, malaria transmission from mosquitos, and surgery for congenital malformations such as hydrocephalus, anal atresia, and cleft lip. Per year, 800–1,000 exposed infants were admitted. Despite sufficient funding and meticulous regulation of care and nutrition, mortality in the hospital during the first month of life was around 70%; the causes were neglected surveillance, cleanliness, and artificial nutrition. The institution persisted for more than 700 years due to numerous connections with the Vatican.