bluuebunny/crossref_metadata_2025_split huggingface dataset:
Applying the win ratio method in clinical trials of orphan drugs: an analysis of data from the COMET trial of avalglucosidase alfa in patients with late-onset Pompe disease
Authors: Boentert Matthias , Berger Kenneth I. , Díaz-Manera Jordi , Dimachkie Mazen M. , Hamed Alaa , Riou França Lionel , Thibault Nathan , Shukla Pragya , Ishak Jack , Caro J. Jaime 
Published: January 2024

Abstract
Background
Clinical trials for rare diseases often include multiple endpoints that capture the effects of treatment on different disease domains. In many rare diseases, the primary endpoint is not standardized across trials. The win ratio approach was designed to analyze multiple endpoints of interest in clinical trials and has mostly been applied in cardiovascular trials. Here, we applied the win ratio approach to data from COMET, a phase 3 trial in late-onset Pompe disease, to illustrate how this approach can be used to analyze multiple endpoints in the orphan drug context.

Methods
All possible participant pairings from both arms of COMET were compared sequentially on changes at week 49 in upright forced vital capacity (FVC) % predicted and six-minute walk test (6MWT). Each participant’s response for the two endpoints was first classified as a meaningful improvement, no meaningful change, or a meaningful decline using thresholds based on published minimal clinically important differences (FVC ± 4% predicted, 6MWT ± 39 m). Each comparison assessed whether the outcome with avalglucosidase alfa (AVA) was better than (win), worse than (loss), or equivalent to (tie) the outcome with alglucosidase alfa (ALG). If tied on FVC, 6MWT was compared. In this approach, the treatment effect is the ratio of wins to losses (“win ratio”), with ties excluded.

Results
In the 2499 possible pairings (51 receiving AVA × 49 receiving ALG), the win ratio was 2.37 (95% confidence interval [CI], 1.30–4.29, p = 0.005) when FVC was compared before 6MWT. When the order was reversed, the win ratio was 2.02 (95% CI, 1.13–3.62, p = 0.018).

Conclusion
The win ratio approach can be used in clinical trials of rare diseases to provide meaningful insight on treatment benefits from multiple endpoints and across disease domains.
The glucocorticoid receptor gene (NR3C1) is linked to and associated with polycystic ovarian syndrome in Italian families
Authors: Syed Shumail , Gragnoli Claudia 
Published: January 2024

Abstract
Objectives
Components of the hypothalamic-pituitary axis (HPA) pathway are potential mediators of the genetic risk of polycystic ovarian syndrome (PCOS). Impaired glucocorticoid receptor (NR3C1) expression and function may underlie impaired HPA-axis cortisol activity, thereby also contributing to the increased adrenal cortisol and androgen production present in women with PCOS. In this study, we aimed to identify whether NR3C1 is linked or in linkage disequilibrium (LD), that is, linkage joint to association, with PCOS in Italian peninsular families.

Method
In 212 Italian families with type 2 diabetes (T2D) from the Italian peninsula, previously recruited for a T2D study and phenotyped for PCOS, we used microarray to genotype 25 variants in the NR3C1 gene. We analyzed the 25 NR3C1 variants by Pseudomarker parametric linkage and LD analysis.

Results
We found the novel implication in PCOS risk of two intronic variants located within the NR3C1 gene (rs10482672 and rs11749561), thereby extending the phenotypic implication related to impaired glucocorticoid receptor.

Conclusions
To the best of our knowledge, this is the first study to report NR3C1 as a risk gene in PCOS.
Deciphering the significance of anoikis in bladder cancer and systematic analysis of S100A7 as a potential therapeutic target
Authors: Wang Haoran , Liu Jianyong , Tang Runhua , Hu Jie , Liu Ming , Wang Jianye , Zhang Jingwen , Hou Huimin 
Published: January 2024

Abstract
Background
Bladder cancer is an epidemic and life-threating urologic carcinoma. Anoikis is a unusual type of programmed cell death which plays a vital role in tumor survival, invasion and metastasis. Nevertheless, the relationship between anoikis and bladder cancer has not been understood thoroughly.

Methods
We downloaded the transcriptome and clinical information of BLCA patients from TCGA and GEO databases. Then, we analyzed different expression of anoikis-related genes and established a prognostic model based on TCGA database by univariate Cox regression, lasso regression, and multivariate Cox regression. Then the Kaplan–Meier survival analysis and receiver operating characteristic (ROC) curves were performed. GEO database was used for external validation. BLCA patients in TCGA database were divided into two subgroups by non-negative matrix factorization (NMF) classification. Survival analysis, different gene expression, immune cell infiltration and drug sensitivity were calculated. Finally, we verified the function of S100A7 in two BLCA cell lines.

Results
We developed a prognostic risk model based on three anoikis-related genes including TPM1, RAC3 and S100A7. The overall survival of BLCA patients in low-risk groups was significantly better than high-risk groups in training sets, test sets and external validation sets. Subsequently, the checkpoint and immune cell infiltration had significant difference between two groups. Then we identified two subtypes (CA and CB) through NMF analysis and found CA had better OS and PFS than CB. Besides, the accuracy of risk model was verified by ROC analysis. Finally, we identified that knocking down S100A7 gene expression restrained the proliferation and invasion of bladder cancer cells.

Conclusion
We established and validated a bladder cancer prognostic model consisting of three genes, which can effectively evaluate the prognosis of bladder cancer patients. Additionally, through cellular experiments, we demonstrated the significant role of S100A7 in the metastasis and invasion of bladder cancer, suggesting its potential as a novel target for future treatments.
Fire regimes of the Southern Appalachians may radically shift under climate change
Authors: Robbins Zachary J. , Loudermilk E. Louise , Mozelewski Tina G. , Jones Kate , Scheller Robert M. 
Published: January 2024

Abstract
Background
Increased drought due to climate change will alter fire regimes in mesic forested landscapes where fuel moisture typically limits fire spread and where fuel loads are consistently high. These landscapes are often extensively modified by human land use change and management. We forecast the influence of varying climate scenarios on potential shifts in the wildfire regime across the mesic forests of the Southern Appalachians. This area has a long history of fire exclusion, land use change, and an expanding wildland urban interface. We considered interactions among climate, vegetation, and anthropogenic influences to forecast future fire regimes and changes to the forest structure. We used climate scenarios representing divergent drought patterns (overall drought trend and interannual variability) within a process-based fire model that captures the influence of climate, fuels, and fire ignition on wildfire patterns and suppression.

Results
Compared to simulations using historical climate (1972–2018), future total burned area (2020–2100: 782,302.7 (716,655.0–847,950.3) ha) increased by 42.3% under high drought variability (1,134,888.4 (1,067,437.2–1,202,339.6) ha), 104.8% under a substantial increase in drought trend (1,602,085.7 (1,511,837.5–1,692,334.0) ha), and 484.7% when combined (4,573,925.0 (4,434,910.5–4,712,939.5) ha). Landscape patterns of fire exclusion and suppression drove the spatial variability of fire return intervals (FRI). Our projections indicate wide spatial variability in future fire regimes with some areas experiencing multiple fires per decade while others experience no fire. More frequent fires corresponded with increased oak prevalence and a reduction in the biomass of mesic hardwoods and maple; however, mesic hardwoods remained prevalent under all fire intervals because of their contemporary dominance.

Conclusions
Our study illustrates how future drought–fire–management interactions and a history of fire exclusion could alter future fire regimes and tree species composition. We find that increasing trends in drought magnitude and variability may increase wildfire activity, particularly in areas with minimal fire suppression. In ecosystems where fuel moisture (and not load) is the standard limitation to fire spread, increased pulses of drought may provide the conditions for more fire activity, regardless of effects on fuel loading. We conclude the effects of climate and human management will determine the novel conditions for both fire regime and ecosystem structure.
Unmasking patient diversity: Exploring cognitive and antidepressive effects of electroconvulsive therapy
Authors: Sellevåg Kjersti , Bartz-Johannessen Christoffer A. , Oedegaard Ketil J. , Nordenskjöld Axel , Mohn Christine , Bjørke Jeanette S. , Kessler Ute 
Published: January 2024

Abstract

Background
Electroconvulsive therapy (ECT) is an established treatment for depression, but more data on effectiveness and safety in clinical practice is needed. The aim of this register-based study was to investigate short-term effectiveness and cognitive safety after ECT, evaluated by clinicians and patients. Secondary, we investigated predictors for remission and cognitive decline.

Methods
The study included 392 patients from the Regional Register for Neurostimulation Treatment in Western Norway. Depressive symptoms and cognitive function were assessed with Montgomery-Åsberg Depression Rating Scale and Mini-Mental State Examination (clinician-rated) and Beck Depression Inventory and Everyday Memory Questionnaire (patient-rated). Assessments were done prior to ECT-series and a mean of 1.7 days after (range 6 days before and 12 days after) end of ECT-series. Paired samples t-tests were extended by detailed, clinically relevant subgroups. Predictors were examined using logistic regression.

Results
Clinician- and patient-rated remission rates were 49.5 and 41.0%, respectively. There was a large reduction in depressive symptoms and a small improvement in cognition after ECT, but we also identified subgroups with non-response of ECT in combination with cognitive decline (4.6% clinician-rated, 15.7% patient-rated). Positive predictors for patient- and clinician-rated remission were increasing age, shorter duration of depressive episode, and psychotic features. Antipsychotic medication at the commencement of treatment and previous ECT-treatment gave higher odds of clinician-rated remission, whereas higher pretreatment subjective depression level was associated with lower odds for patient-rated remission. Clinician-rated cognitive decline was predicted by higher pretreatment MMSE scores, whereas psychotic features, increasing age, and greater pretreatment subjective memory concerns were associated with lower odds for patient-rated cognitive decline.

Conclusions
Our study supports ECT as an effective and safe treatment, although subgroups have a less favorable outcome. ECT should be considered at an early stage for older patients suffering from depression with psychotic features. Providing comprehensive and balanced information from clinicians and patients perspectives on effects and side effects, may assist in a joint consent process.
Phase Angle of Bioelectrical Impedance Analysis as an Indicator for Diabetic Polyneuropathy in Type 2 Diabetes Mellitus
Authors: Schimpfle Lukas , Tsilingiris Dimitrios , Mooshage Christoph M , Kender Zoltan , Sulaj Alba , von Rauchhaupt Ekatherina , Szendroedi Julia , Herzig Stephan , Goepfert Jens , Groener Jan , Nawroth Peter P , Bendszus Martin , Heiland Sabine , Kurz Felix T , Jende Johann M E , Kopf Stefan 
Published: January 2024

Abstract

Context
Due to the heterogenous clinical symptoms and deficits, the diagnosis of diabetic polyneuropathy (DPN) is still difficult in clinical routines, leading to increased morbidity and mortality.

Objective
We studied the correlation of phase angle (PhA) of bioelectrical impedance analysis (BIA) with clinical, laboratory, and physical markers of DPN to evaluate PhA as a possible diagnostic method for DPN.

Materials and methods
In this cross-sectional observational study as part of the Heidelberg Study on Diabetes and Complications, we examined 104 healthy individuals and 205 patients with type 2 diabetes mellitus (T2D), among which 63 had DPN. The PhA was calculated from multifrequency BIA. Nerve conduction studies, quantitative sensory testing (QST) and diffusion-weighted magnetic resonance neurography to determine fractional anisotropy (FA) reflecting peripheral nerve integrity were performed.

Results
T2D patients with DPN had lower PhA values (5.71 ± 0.10) compared to T2D patients without DPN (6.07 ± 0.08, P = .007, + 6.1%) and healthy controls (6.18 ± 0.08, P &lt; .001, + 7.9%). Confounder-adjusted analyses showed correlations of the PhA with conduction velocities and amplitudes of the peroneal (β=.28; β=.31, P &lt; .001) and tibial nerves (β=.28; β=.32, P &lt; .001), Z-scores of QST (thermal detection β=.30, P &lt; .05) and the FA (β=.60, P &lt; .001). Receiver-operating characteristic analysis showed similar performance of PhA in comparison to the mentioned diagnostic methods.

Conclusion
The study shows that PhA is, in comparison to other test systems used, at least an equally good and much easier to handle investigator-independent marker for detection of DPN.
P-01 Case report of adrenal insufficiency due to bilateral adrenal hemorage
Authors: Korkmaz Elif Seray , Gökçe Birsen Öztürk , Nur Kebapçı Medine , Yorulmaz Göknur 
Published: January 2024

Abstract

Introduction
Arterial or venous thrombosis may be seen in the presence of antiphospholipid antibody (AFA). Rarely, it can cause adrenal hemorrhage. In this case, a 39-year-old case of adrenal insufficiency due to adrenal hemorrhage accompanied by AFA is presented.

Clinical Case
A 39-year-old male patient with no known disease was admitted to the emergency service with complaints of abdominal pain, general condition disorder, weakness, nausea and vomiting. Hypotension, Na:121meq/L (136-145 meq/L) and K:6.2 meq/L (3.5-5 meq/L), creatinine: 3.56 mg/dl (0.7-1.20), urea: 50.5 mg /dl (6-20), cortisol value measured by suspecting acute adrenal insufficiency was 1.42 µg/dL (5-25 µg/dL), ACTH value was 561 pg/mL (10-46 pg/mL). Abdominal CT for abdominal pain showed a collection area of 58 mm ap diameter on the right and 66 mm ap diameter on the left in both surrenal lobes, and numerous millimeter-sized hypointense areas in the subcapsular area of both kidneys and were evaluated as significant in terms of microinfarcts. Then, areas that were hyperdense in the precontrast series and did not show significant enhancement in the postcontrast series were evaluated for bleeding in adrenal CT (Figure 1).In the tests performed, aPTT 44.5 sec (24-40), C3 1.272 g/dL (0.9-1.8 g/dL), ANA:1/160 homogeneous positive granular, anti-dsDNA:28 IU/mL, lupus anticoagulation positive, in complete urinalysis proteinuria and hyaline cast were detected. The patient was diagnosed with AFAS and systemic lupus erythematosus (SLE), and hydroxychloroquine was started. Warfarin and acetylsalicylic acid were started due to renal vein thrombosis. Stress-dose steroid therapy (80 mg/day methylprednisolone) was started in the patient who was suspected of having adrenal insufficiency due to adrenal hemorrhage. The hemorrhage in our patient was attributed to the hemorrhage caused by the AFA-related infarction. The patient who completed the treatment was discharged with 200 mg hydroxychloroquine, 30 mg hydrocortisone, 0.5 mg fludrocortisone, 5 mg warfarin, 100 mg acetylsalicylic acid, 10 mg amlodipine.

Conclusion
Although the pathogenetic mechanism of adrenal insufficiency seen in AFA syndrome is not fully known; increased coagulation status in these patients is held responsible. Adrenal insufficiency is thought to be due to hemorrhage after venous thrombosis at the adrenal vein or microvascular level. AFA-related adrenal insufficiency is usually permanent and rarely resolves. Therefore, long-term follow-up of these patients is required. The presence of AFA should be investigated in patients presenting with bilateral adrenal hemorrhage.Figure 1.Sürrenal bt
P-03 A report of recurring pregnancy-induced Cushing's Syndrome
Authors: Niafar Mitra , Bahrami Amir , Ghorbani Fatemeh , Aghamohammadzadeh Naser , Sadra Vahideh , Djala Nader Nader 
Published: January 2024

Abstract

Introduction
The incidence of pregnancy-induced Cushing's syndrome (CS) is very low. However, the diagnosis of CS in pregnant patients is very difficult because of an overlapping signs and symptoms.

Clinical Case
A 20-year-old woman with polycystic ovarian syndrome (PCOS) was successfully treated with clomiphene for infertility and pregnant in September of 2016 for the first time. She experienced out of proportion abdominal obesity, excessive striosis, exacerbation of hirsutism and myasthenia during the first trimester of her pregnancy. Initial diagnosis of ovarian hyperstimulation syndrome (OHSS) was made and due to concomitant intrauterine growth retardation (IUGR), the pregnancy was electively terminated at the 8th week. All associated symptoms spontaneously regressed within 2-3 months after the abortion. The second pregnancy was induced with a pulse treatment of letrozole 5 mg, followed by 3 every other day injections of 100 units recombinant follicle-stimulating hormone. Within the first 4 weeks into the second pregnancy, the patient developed recurrence of OHSS symptoms. In addition to the prior symptoms and progressive proximal myasthenia, the patient developed hypertension, round moon-like face, back hump, and suprasternal fat pad consistent with the typical features of CS. In week 14 of pregnancy, the patient complained from acute-onset bilateral blindness and hypertension (blood pressure of 180/120 mmHg), which soon progressed into loss of consciousness and grand-mal seizure. She was admitted to the intensive care unit (ICU). Admission laboratory testing included those to assess the function of the pituitary-adrenal axis (HPA) due to the presence of symptoms related to CS. Based on available clinical information a diagnosis of hemolysis, elevated liver enzymes, and a low platelet count (HELLP) syndrome was made and emergency termination of pregnancy was carried out at the gestational age of 14 weeks. The patient`s clinical signs such as hypertension and acute blindness were totally subsided soon after the therapeutic abortion. Diagnosis of ACTH independent CS was made based on elevated 8 a.m. serum cortisol level unresponsive to low-dose dexamethasone (45-41 µg/ dL).

Conclusion
Diagnosis of CS in pregnancy is challenging as the physiological changes during pregnancy may mimic those of CS. Long-term treatment of gestational CS has not been as successful. However, in the case of adrenal hyperplasia, bilateral adrenalectomy offers a certain cure. Our patient had a therapeutic abortion due to severe maternal complications and development of CS during the early gestational age. The patient was reeducated on the subject of contraception and the possibility of adrenalectomy for future pregnancies. Due to the temporal relation between the occurrence of CS after each pregnancy the diagnosis of gestational hypercortisolism was made, and for further pregnancies bilateral adrenalectomy was recommended.
P-06 Catecholamine-induced cardiomyopathy: A rare presentiation of pheochromocytoma
Authors: Bağır Gülay Şimşek , Haydardedeoğlu Fi̇li̇z , Bakiner Okan , Yabanoğlu Hakan , Torun Neşe , Koçer Emrah , Gürkan Hakan , Ertörer Melek Eda 
Published: January 2024

Abstract

Introduction
Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors. Clinical manifestations consist of various cardiovascular signs and symptoms related to excessive secretion of catecholamines. Catecholamine-induced cardiomyopathy is a rare but life-threatening complication of PPGL. Excessive discharge of catecholamines results in vasoconstriction, coronary vasospasm and myocardial ischemia. Three types of cardiomyopathies can be observed in patients with PPGL; dilated cardiomyopathy, Takotsuba cardiomyopathy and hypertrophic cardiomyopathy.

Clinical Case
Herein, we present a case with PPGL complicated with heart failure probably due to excessive secretion of catecholamines. A 19 years-old man was admitted to emergency department with dyspnea and hypotension. He exhibited severe signs of heart failure with very high liver function tests; ALT: 3647 U/L (8-65) and AST: 4542U/L (7-40), probably due to hepatic congestion. Echocardiogram performed in ICU reported %10 left venticular ejection fraction with diffuse akinesia. Remarkable improvement of liver function was recorded following the introduction of heart failure medicines. A computed tomography scan that was performed for abdominal pain and distension revealed a six cm tumour at the left adrenal gland compatible with pheochromocytoma. Laboratory analyses were; 24-hour urine metanephrines: 1938mcg (44-261), normetanephrines: 17934mcg (103-390). Following necessary preoperative preparations, laparoscopic left adrenalectomy was performed and a 70 mm adrenal tumor, histopathologically compatible with pheochromocytoma, was excised. His postoperative laboratory findings were; 24-hour urine metanephrines: 248 mcg (44-261), normetanephrines: 4368 mcg (103-390), chromogranin A: 554.9 ng/ml (0-100), 3-methoxytyramine: 0.34 nmol/l (0-0.17). A 68-Ga-DOTA-Peptide PET/CT following 12 weeks of surgery demonstrated hypermetabolic lesions at left suprarenal area. A second open surgery was performed and lymph node metastases were detected (Figure 1). His cardiac functions ameliorated significantly following the removal of tumors. Genetic analysis for PPGL syndromes were negative for KIF1B, SDHB, NTRK1, TMEME127, VHL, RET, SDHD genes. Work-up is still pending for the mutations of SDHA, SDHC and SDHAF2 genes.

Conclusion
Cathecolamine-induced cardiomyopathy is a rare entity associated with PPGL. Urgent recognition of related clinical signs and symptoms and detection of PPGL is lifesaving. It should be kept in mind in patients presenting with symptoms of heart failure, hypotension and multisystem crisis in the absence of coronary or valvular heart disease.Figure 1.Pheochromocytoma with lymph node metastasis. (H&E x100)