Miracle-dz/UniFAR-FTUs huggingface dataset:
Avacopan for the treatment of ANCA-associated vasculitis

ABSTRACT Introduction: Anti-neutrophil cytoplasm autoantibodies (ANCA)-associated vasculitides (AAVs) are a group of rare heterogeneous diseases characterized by blood vessel inflammation resulting in organ destruction and death. Although various treatment strategies have resulted in marked improvement in vasculitis-specific outcomes, many patients with AAV continue to suffer from complications related to the prolonged use of glucocorticoids (GC) such as infections, metabolic abnormalities, and increased cardiovascular morbidity. Recently, activation of the alternative complement pathway has been implicated in the augmentation of the damage caused by AAV via the complement C5a receptor (C5aR1, CD88). Specifically targeting this pathway may lead to improved outcomes in patients with AAV. Areas covered: In this article, we have summarized the rationale for targeting the complement pathway in AAV. The relevant pre-clinical, phase I, II and III findings with emphasis on the efficacy, and safety of avacopan, a new oral competitive inhibitor that interferes with the binding of C5a to C5aR1 (CD88), are reviewed. Expert opinion: These results are encouraging, may led to major changes in the treatment approach for AAV, and give rise to future studies utilizing complement inhibitors in AAV patients, and potentially in other immune mediated diseases.
The Use of Machine Learning Techniques to Determine the Predictive Value of Inflammatory Biomarkers in the Development of Type 2 Diabetes Mellitus.

Background: Certain inflammatory biomarkers, such as interleukin-6, interleukin-1, C-reactive protein (CRP), and fibrinogen, are prototypical acute-phase parameters that can also be predictors of cardiovascular disease. However, this inflammatory response can also be linked to the development of type 2 diabetes mellitus (T2DM). Methods: We performed a cross-sectional, retrospective study of hypertensive patients in an outpatient setting. Demographic, clinical, and laboratory parameters, such as the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), CRP, and fibrinogen, were recorded. The outcome was progression to overt T2DM over the 12-year observation period. Results: A total of 3,472 hypertensive patients were screened, but 1,576 individuals without T2DM were ultimately included in the analyses. Patients with elevated fibrinogen, CRP, and insulin resistance had a significantly greater incidence of progression to T2DM. During follow-up, 199 patients progressed to T2DM. Multivariate logistic regression analyses showed that body mass index [odds ratio (OR) 1.04, 95% confidence interval (CI): 1.01-1.07], HOMA-IR (OR 1.13, 95% CI: 1.08-1.16), age (OR 1.05, 95% CI: 1.03-1.07), log(CRP) (OR 1.37, 95% CI: 1.14-1.55), and fibrinogen (OR 1.44, 95% CI: 1.23-1.66) were the most important predictors of progression to T2DM. The area under the receiver operating characteristic curve (AUC) of this model was 0.76. Using machine learning methods, we built a model that included HOMA-IR, fibrinogen, and log(CRP) that was more accurate than the logistic regression model, with an AUC of 0.9. Conclusion: Our results suggest that inflammatory biomarkers and HOMA-IR have a strong prognostic value in predicting progression to T2DM. Machine learning methods can provide more accurate results to better understand the implications of these features in terms of progression to T2DM. A successful therapeutic approach based on these features can avoid progression to T2DM and thus improve long-term survival.
Delayed kidney transplantation in combined liver-kidney transplantation

Purpose of review To review the impact of delayed kidney transplantation approach in combined (simultaneous) liver-kidney transplantation (CLKT). Recent findings CLKT offers a life-saving procedure for patients with both end-stage liver disease and chronic kidney disease or prolonged acute kidney injury. It is the most common multiorgan transplant procedure in the US accounting for 9–10% of all liver transplants performed. The number of CLKT has also been increasing in other countries with a better understanding of hepato-renal syndrome. US is the only country which implemented a national allocation policy for CLKT in 2017. Due to the different physiological needs of liver and kidney allografts immediately after transplantation, delayed kidney transplantation approach in CLKT has been introduced for the first time by the Indiana Group, naming it as ‘the Indiana Approach’. Over the years, many other groups in the US and in Europe published better outcomes in CLKT using the delayed kidney transplantation approach with the support of hypothermic machine perfusion. Summary Several groups have shown that delayed kidney transplantation in CLKT is a safe procedure with better outcomes in graft(s) and patient survival.
Complications and Revisions After Spine Surgery in Patients With Skeletal Dysplasia: Have We Improved?

Study Design: Retrospective case series. Objective: To report contemporary rates of complications and subsequent surgery after spinal surgery in patients with skeletal dysplasia. Methods: A case series of 25 consecutive patients who underwent spinal surgery between 2007 and 2017 were identified from a single institution’s skeletal dysplasia registry. Patient demographics, medical history, surgical indication, complications, and subsequent surgeries (revisions, extension to adjacent levels, or for pathology at a non-contiguous level) were collected. Charlson comorbidity indices were calculated as a composite measure of overall health. Results: Achondroplasia was the most common skeletal dysplasia (76%) followed by spondyloepiphyseal dysplasia (20%); 1 patient had diastrophic dysplasia (4%). Average patient age was 53.2 ± 14.7 years and most patients were in excellent cardiovascular health (88% Charlson Comorbidity Index 0-4). Mean follow up after the index procedure was 57.4 ± 39.2 months (range). Indications for surgery were mostly for neurologic symptoms. The most commonly performed surgery was a multilevel thoracolumbar decompression without fusion (57%). Complications included durotomy (36%), neurologic complication (12%), and infection requiring irrigation and debridement (8%). Nine patients (36%) underwent a subsequent surgery. Three patients (12%) underwent a procedure at a non-contiguous anatomic zone, 3 (12%) underwent a revision of the previous surgery, and another 3 (12%) required extension of their previous decompression or fusion. Conclusions: Surgical complication rates remain high after spine surgery in patients with skeletal dysplasia, likely attributable to inherent characteristics of the disease. Patients should be counseled on their risk for complication and subsequent surgery.
Estimating spatial variation in the effects of climate change on the net primary production of Japanese cedar plantations based on modeled carbon dynamics

Spatiotemporal prediction of the response of planted forests to a changing climate is increasingly important for the sustainable management of forest ecosystems. In this study, we present a methodology for estimating spatially varying productivity in a planted forest and changes in productivity with a changing climate in Japan, with a focus on Japanese cedar (Cryptomeria japonica D. Don) as a representative tree species of this region. The process-based model Biome-BGC was parameterized using a plant trait database for Japanese cedar and a Bayesian optimization scheme. To compare productivity under historical (1996–2000) and future (2096–2100) climatic conditions, the climate scenarios of two representative concentration pathways (i.e., RCP2.6 and RCP8.5) were used in five global climate models (GCMs) with approximately 1-km resolution. The seasonality of modeled fluxes, namely gross primary production, ecosystem respiration, net ecosystem exchange, and soil respiration, improved after two steps of parameterization. The estimated net primary production (NPP) of stands aged 36–40 years under the historical climatic conditions of the five GCMs was 0.77 ± 0.10 kgC m-2 year-1 (mean ± standard deviation), in accordance with the geographical distribution of forest NPP estimated in previous studies. Under the RCP2.6 and RCP8.5 scenarios, the mean NPP of the five GCMs increased by 0.04 ± 0.07 and 0.14 ± 0.11 kgC m-2 year-1, respectively. The increases in annual NPP were small in the southwestern region because of the decreases in summer NPP and the small increases in winter NPP under the RCP2.6 and RCP8.5 scenarios, respectively. Under the RCP2.6 scenario, Japanese cedar was at risk in the southwestern region, in accordance with previous studies, and monitoring and silvicultural practices should be modified accordingly.
Utilization of biotechnological drugs in rare diseases requiring the use of off-label drugs in children in Turkey

Background/aim Pediatric patients, especially those with rare diseases, represent a population that has a high tendency towards off-label drug use (OLDU) and needs a more careful practice of pharmacotherapy than in adults. We aimed to investigate biotechnological drug use in children with rare diseases requiring OLDU. Materials and methods This retrospective study examined all single-diagnosed OLDU applications (n = 5792) for 4992 children (<18-year) in Turkey. Applications of rare diseases were selected, and their descriptive characteristics were examined, including demographic features of patients, biotechnological drug utilization status, and disease categories. The off-label statuses of the drugs at the end of 2020 were also examined. Results In total, 77.7% (n = 4501) of OLDU applications were made for rare diseases. Biotechnological drug use was higher in rare disease applications than in nonrare diseases (37.9% vs. 19.2%, respectively; p < 0.0001). Canakinumab was the top applied biotechnological drug (73.2%). Compared to that in small-molecule drugs, the mean age of patients was higher in biotechnological drug-containing applications (8.1 ± 5.3 vs. 9.7 ± 4.9, respectively; p < 0.0001). Biotechnological drug use was higher in nonneoplastic rare diseases (40.3%) than in neoplastic rare diseases (26.4%), (p < 0.0001). At the end of 2020, the approval status of the off-label indications covered in 2016 was significantly higher for rare (24.4%) vs. nonrare (5.2%, p < 0.0001) diseases and for biotechnological (32.3%) vs. small-molecule (13.9%, p < 0.0001) drugs. In total, 87.7% of the drugs would have to be still used in the off-label setting at the end of 2020. Conclusion It was seen that more than three-quarters of the pediatric OLDU applications are for rare diseases, and the need for biotechnological OLDU in this group is almost 2-fold of small-molecule drug use. While further projected findings imply a higher approval tendency for rare diseases and biotechnological drugs, there seems to be more room for improvement for pediatric drug use.
Association of hypogonadism symptoms and serum hormones in aging males

The association between hypogonadism symptoms and the levels of serum hormones are still in debate. To investigate the relationship between hypogonadism symptoms and serum hormones in middle‐aged and elderly Chinese men, this community‐based cross‐sectional study was conducted based on a total of 965 ageing men. The ageing males’ symptom (AMS) scale, International Index of Erectile Function‐5 (IIEF‐5), International Prostate Symptom Score (IPSS) questionnaires and related variables were assessed. Blood tests for total testosterone (TT), sex hormone‐binding globulin (SHBG) and luteinising hormone (LH) were performed. Serum level of free testosterone (FT) and bioavailable testosterone (Bio‐T) was calculated. The mean age was 56.34 ± 8.85 years. Total AMS score was significantly associated with all five serum hormones (LH: p < 0.001; SHBG: p < 0.001; TT: p =.043; FT: p = 0.007; Bio‐T: p < 0.001). We identified sexual and somatic symptoms were obviously related to five serum hormones, while psychological symptoms seemed to have no association with serum hormones. After adjusting for age and BMI, multiple linear regression analysis indicated that LH had positive correlations with total AMS score, somatic and sexual symptom score (p < 0.05). In conclusion, LH and SHBG had the strongest correlation hypogonadism and might be used as early predictors for symptomatic hypogonadism in the near future.
Exploring how mothers of a child with a genetic disorder experience their couple relationship in a low socio‐economic setting

Having a child with a genetic disorder directly impacts a couple's relationship due to increased care demands. Most research on couple relationships in the context of having a child with a disability has been done in well‐resourced, developed countries. In South Africa, the black South African population has been historically disadvantaged resulting in high rates of unemployment and poverty, and disruption of the family system. The purpose of this study was to explore the impact of having a child with a genetic disorder on the couple relationship in a low socio‐economic setting. Thirteen black South African mothers of a child with a confirmed or suspected genetic disorder participated in the study. All participants were recruited while waiting to be seen for a follow‐up appointment by a medical geneticist at a Genetic Clinic in Johannesburg, South Africa between 2016 and 2019. Data were collected through semi‐structured interviews lasting between 25 and 60 min and analyzed using thematic content analysis. Findings showed that mothers of a child with a genetic disorder in this low socio‐economic setting frequently felt unsupported and carried the responsibility of childcare alone. The majority of participants wanted more tangible and emotional support from their partners and without this support they felt isolated and alone. The participants used many different coping strategies to deal with the distress of having a child with a genetic disorder but most frequently they described using 'acceptance'. Participants' partners were more often reported to use escape‐avoidance strategies such as abandonment, denying paternity, withdrawal, and partner‐blame. We suggest that mothers of a child with a genetic disorder should consult with a genetic counselor in addition to a medical geneticist to enable the provision of emotional support.
Current Status of Endovascular Treatment for Acute Large Vessel Occlusion in China

Supplemental Digital Content is available in the text. Background and Purpose: The benefit of endovascular treatment (EVT) for large vessel occlusion in clinical practice in developing countries like China needs to be confirmed. The aim of the study was to determine whether the benefit of EVT for acute ischemic stroke in randomized trials could be generalized to clinical practice in Chinese population. Methods: We conducted a prospective registry of EVT at 111 centers in China. Patients with acute ischemic stroke caused by imaging-confirmed intracranial large vessel occlusion and receiving EVT were included. The primary outcome was functional independence at 90 days defined as a modified Rankin Scale score of 0 to 2. Outcomes of specific subgroups in the anterior circulation were reported and logistic regression was performed to predict the primary outcome. Results: Among the 1793 enrolled patients, 1396 (77.9%) had anterior circulation large vessel occlusion (median age, 66 [56–73] years) and 397 (22.1%) had posterior circulation large vessel occlusion (median age, 64 [55–72] years). Functional independence at 90 days was reached in 45% and 44% in anterior and posterior circulation groups, respectively. For anterior circulation population, underlying intracranial atherosclerotic disease was identified in 29% of patients, with higher functional independence at 90 days (52% versus 44%; P=0.0122) than patients without intracranial atherosclerotic disease. In the anterior circulation population, after adjusting for baseline characteristics, procedure details, and early outcomes, the independent predictors for functional independence at 90 days were age <66 years (odds ratio [OR], 1.733 [95% CI, 1.213–2.476]), time from onset to puncture >6 hours (OR, 1.536 [95% CI, 1.065–2.216]), local anesthesia (OR, 2.194 [95% CI, 1.325–3.633]), final modified Thrombolysis in Cerebral Infarction 2b/3 (OR, 2.052 [95% CI, 1.085–3.878]), puncture-to-reperfusion time ≤1.5 hours (OR, 1.628 [95% CI, 1.098–2.413]), and National Institutes of Health Stroke Scale score 24 hours after the procedure <11 (OR, 9.126 [95% CI, 6.222–13.385]). Conclusions: Despite distinct characteristics in the Chinese population, favorable outcome of EVT can be achieved in clinical practice in China. Registration: URL: https://www.clinicaltrials. gov; Unique identifier: NCT03370939.
Strong self-trapping by deformation potential limits photovoltaic performance in bismuth double perovskite

Bismuth double perovskite Cs2AgBiBr6 strong electron–acoustic phonon interactions derail its photovoltaic aspirations. Bismuth-based double perovskite Cs2AgBiBr6 is regarded as a potential candidate for low-toxicity, high-stability perovskite solar cells. However, its performance is far from satisfactory. Albeit being an indirect bandgap semiconductor, we observe bright emission with large bimolecular recombination coefficient (reaching 4.5 ± 0.1 × 10−11 cm3 s−1) and low charge carrier mobility (around 0.05 cm2 s−1 V−1). Besides intermediate Fröhlich couplings present in both Pb-based perovskites and Cs2AgBiBr6, we uncover evidence of strong deformation potential by acoustic phonons in the latter through transient reflection, time-resolved terahertz measurements, and density functional theory calculations. The Fröhlich and deformation potentials synergistically lead to ultrafast self-trapping of free carriers forming polarons highly localized on a few units of the lattice within a few picoseconds, which also breaks down the electronic band picture, leading to efficient radiative recombination. The strong self-trapping in Cs2AgBiBr6 could impose intrinsic limitations for its application in photovoltaics.
Dorsal and ventral mossy cells differ in their axonal projections throughout the dentate gyrus of the mouse hippocampus

Glutamatergic hilar mossy cells (MCs) have axons that terminate both near and far from their cell body but stay within the DG, making synapses primarily in the molecular layer. The long‐range axons are considered the primary projection, and extend throughout the DG ipsilateral to the soma, and project to the contralateral DG. The specificity of MC axons for the inner molecular layer (IML) has been considered to be a key characteristic of the DG. In the present study, we made the surprising finding that dorsal MC axons are an exception to this rule. We used two mouse lines that allow for Cre‐dependent viral labeling of MCs and their axons: dopamine receptor D2 (Drd2‐Cre) and calcitonin receptor‐like receptor (Crlr‐Cre). A single viral injection into the dorsal DG to label dorsal MCs resulted in labeling of MC axons in both the IML and middle molecular layer (MML). Interestingly, this broad termination of dorsal MC axons occurred throughout the septotemporal DG. In contrast, long‐range axons of ventral MCs terminated in the IML, consistent with the literature. Taken together, these results suggest that dorsal and ventral MCs differ significantly in their axonal projections. Since MC projections in the ML are thought to terminate primarily on GCs, the results suggest a dorsal–ventral difference in MC activation of GCs. The surprising difference in dorsal and ventral MC projections should therefore be considered when evaluating dorsal–ventral differences in DG function.
An Intrinsic Relationship between Molecular Structure in Self-Assembled n-Alkylsiloxane Monolayers and Deposition Temperature

We have studied the effect of preparation temperature, in the range 5-65 OC, on the structures of n-octadecylsiloxane monolayers prepared by self-assembly from dilute solution of n-octadecyltrichlorosilane onto the surface of freshly hydrated, oxidized silicon substrates. Structural features of the films were characterized using a combination of liquid drop contact angle measurements, null ellipsometry, and infrared transmission spectroscopy. The contact angle data confirm a previously reported observation of a critical temperature, Tc - 28 f 5 OC, below which the surface energy is constant at a near-limiting value of a pure CH3 surface and above which the surface energy monotonically increases with increasing temperature. Coverages and chain organization, as measured by ellipsometry and vibrational spectroscopic features (peak positions and integrated intensities of methylene C-H stretching modes), respectively, show changes in the same temperature region as the wetting behavior. We conclude that when prepared below T,, the films exhibit a heterogeneous structure with closely spaced islands of densely packed, nearly all-trans alkyl chains arranged nearly vertical to the surface. In contrast, when prepared above T,, the films exhibit monotonically diminishing coverage with increasing preparation temperature and the alkyl chains increasingly assume higher contents of conformational disorder. Further, the infrared data indicate that these higher temperature films are heterogeneous with coexisting domains of high and low chain conformational ordering. All the data, taken together, are in good conformity with a film formation mechanism which involves, prior to siloxy group cross-linking, the intervention of intermediate structural phases of mobile alkylsiloxy species adsorbed on a water layer adjacent to the solid substrate surface. In support of this mechanism, a strong parallel is apparent between Tc and the triple point temperature at which gas (G), liquid-expanded (LE), and liquid-condensed (LC) phases coexist for chain Langmuir monolayers at the air/bulk water interface. Below Tc the self-assembled film structure is similar to that of the nearly pure LC Langmuir phase while above Tc the film structure is similar to that of coexisting LE and LC phases. Deviations of the self-assembled film structures for the analogous equilibrium Langmuir phase structures occur at higher preparation temperatures and are rationalized in terms of both the known occurrence of nonequilibrium phases in Langmuir films above the triple point temperature and the relative acceleration of the Si-O-Si cross-linking reaction in the self-assembled film to form structures with frozen-in defects.