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2022 ◽  
Vol 23 (1) ◽  
Author(s):  
Yngvar Lunde Haaskjold ◽  
Rune Bjørneklett ◽  
Leif Bostad ◽  
Lars Sigurd Bostad ◽  
Njål Gjærde Lura ◽  
...  

Abstract Background The Oxford classification/MEST score is an established histopathologic scoring system for patients with IgA nephropathy (IgAN). The objective of this study was to derive a prognostic model for IgAN based on the MEST score and histopathologic features. Methods A total of 306 patients with biopsy-proven primary IgAN were included. Histopathologic samples were retrieved from the Norwegian Kidney Biopsy Registry and reclassified according to the Oxford classification. The study endpoint was end-stage renal disease (ESRD). Patients were subclassified into three risk models based on histologic features (Model A), a composite score calculated from the adjusted hazard ratio values (Model B), and on quartiles (Model C). Results The mean follow-up time was 16.5 years (range 0.2–28.1). In total, 61 (20%) patients reached ESRD during the study period. Univariate analysis of M, E, S, T and C lesions demonstrated that all types were associated with an increased risk of ESRD; however, a multivariate analysis revealed that only S, T and C lesions were associated with poor outcomes. Statistical analysis of 15-year data demonstrated that Models A and B were as predictive as the MEST score, with an area-under-the-curve at 0.85. The Harrel c index values were 0.81 and 0.80 for the MEST score and Models A and B, respectively. In the present cohort, adding C lesions to the MEST score did not improve the models prognostic value. Conclusions Patients can be divided into risk classes based on their MEST scores. Histopathologic data provide valuable prognostic information at the time of diagnosis. Model B was the most suitable for clinical practice because it was the most user-friendly.


PLoS ONE ◽  
2022 ◽  
Vol 17 (1) ◽  
pp. e0262046
Author(s):  
Allison A. Fuchs ◽  
Praveen K. Balne ◽  
Elizabeth A. Giuliano ◽  
Nishant R. Sinha ◽  
Rajiv R. Mohan

Corneal injury and aberrant wound healing commonly result in corneal fibrosis and subsequent vision loss. Intermediate-conductance calmodulin/calcium-activated K+ channels (KCa3.1) have been shown to promote fibrosis in non-ocular and ocular tissues via upregulation of transforming growth factor beta (TGFβ). TRAM-34 is a selective inhibitor of KCa3.1 and reduces fibrosis by downregulation of TGFβ-induced transdifferentiation of stromal fibroblasts to myofibroblasts. Ascorbic acid has been demonstrated to be effective in promoting corneal re-epithelialization and reduction of neovascularization via anti-VEGF and anti-MMP mechanisms. This study evaluates tolerability and efficacy of a novel combination of TRAM-34 (25μM) and ascorbic acid (10%) topical treatment for corneal fibrosis using an established in vivo rabbit model and conducting clinical eye examinations. Markers of corneal fibrosis were evaluated in all corneas at study endpoint via histopathology, immunofluorescence, and quantitative real-time PCR. The eyedrop treated eyes showed significantly improved clinical outcomes based on modified McDonald Shadduck scores, reduction of clinical haze on Fantes scores, and reduction of central corneal thickness (CCT). At cellular and molecular levels, eyedrop treatment also significantly reduced expression of alpha smooth muscle actin (α-SMA) mRNA and protein, collagen III mRNA, and fibronectin mRNA compared to non-treated eyes. Our study suggests that a tested new bimodal eyedrop is well tolerated and effectively reduces corneal fibrosis/haze in rabbits in vivo.


Author(s):  
Christoph Seidel ◽  
Marcus Hentrich ◽  
Stefanie Zschäbitz ◽  
Pia Paffenholz ◽  
Axel Heidenreich ◽  
...  

Abstract Purpose To report on the clinical characteristics, outcome, and frequency of peritoneal carcinosis (PC) in patients with advanced germ cell tumors (GCT), a multicenter registry analysis was carried out. Methods A multicenter registry analysis was conducted by the German Testicular Cancer Study Group (GTCSG) with international collaborators. Data was collected and analyzed retrospectively. Patients were eligible for inclusion if PC was diagnosed either by radiologic or histopathologic finding during the course of disease. Descriptive and explorative statistical analysis was carried out with cancer-specific survival (CSS) as primary study endpoint. Results Collaborators from ten GCT expert centers identified 28 GCT (0.77%) patients with PC after screening approximately 3767 GCT patient files and one case was contributed from a cancer registry request. Patients were diagnosed from 1997 to 2019 at a median age of 37 years (interquartile range, 13). Two patients (7%) presented with stage I and 27 patients (93%) with synchronous metastatic disease at first diagnosis. The primary histology was seminoma in seven (27%) and non-seminoma in 21 patients (72%). PC was detected after a median of 15.3 months from primary diagnosis (range 0–177) and two consecutive treatment lines (range 0–5), respectively. The median CSS from the time of detection of PC was 10.5 months (95%Confidence Interval 0.47–1.30) associated with an overall 2-year CSS rate of 30%. Conclusion PC represents a rare tumor manifestation in GCT patients and was primarily associated with the occurrence of advanced cisplatin-refractory disease conferring to a dismal prognosis.


Trials ◽  
2022 ◽  
Vol 23 (1) ◽  
Author(s):  
C. A. J. Oudmaijer ◽  
R. C. Minnee ◽  
R. A. Pol ◽  
W. M. C. van den Boogaard ◽  
D. S. J. Komninos ◽  
...  

Abstract Background One of the main effectors on the quality of life of living-kidney donors is postoperative fatigue. Caloric restriction (CR) and short-term fasting (STF) are associated with improved fitness and increased resistance to acute stress. CR/STF increases the expression of cytoprotective genes, increases immunomodulation via increased anti-inflammatory cytokine production, and decreases the expression of pro-inflammatory markers. As such, nutritional preconditioning by CR or STF represents a non-invasive and cost-effective method that could mitigate the effects of acute surgery-induced stress and postoperative fatigue. To investigate whether preoperative STF contributes to a reduction in fatigue after living-kidney donation, a randomized clinical trial is indicated. Methods We aim to determine whether 2.5 days of fasting reduces postoperative fatigue score in subjects undergoing living-kidney donation. In this randomized study, the intervention group will follow a preoperative fasting regime for 2.5 days with a low-dose laxative, while the control group will receive standard care. The main study endpoint is postoperative fatigue, 4 weeks after living-kidney donation. Secondary endpoints include the effect of preoperative fasting on postoperative hospital admission time, the feasibility of STF, and the postoperative recovery of donor and recipient kidney function. This study will provide us with knowledge of the feasibility of STF and confirm its effect on postoperative recovery. Discussion Our study will provide clinically relevant information on the merits of caloric restriction for living-kidney donors and recipients. We expect to reduce the postoperative fatigue in living-kidney donors and improve the postoperative recovery of living-kidney recipients. It will provide evidence on the clinical merits and potential caveats of preoperative dietary interventions. Trial registration Netherlands Trial Register NL9262. EudraCT 2020-005445-16. MEC Erasmus MC MEC-2020-0778. CCMO NL74623.078.21


2021 ◽  
Author(s):  
Gabriel Roman Souza ◽  
Ahmed Abdalla ◽  
Sukeshi Patel Arora ◽  
Daruka Mahadevan

Abstract We analyzed the outcomes of patients in our institution treated with off-label drugs targeting actionable genomic alteration based on next-generation sequencing when clinical trials were not available. Our study endpoint was objective tumor response or stable disease at 16 weeks or later after treatment initiation. Sixteen patients were included in this study, 8 were treated with immune checkpoint inhibitors targeting PD-L1 or TP53 mutations and 8 with other drugs. Tumors were analyzed based on PD-L1 expression, TP53 mutation, MSI, TMB, MMR status, and other targetable alterations. Of the 16 patients in the intention-to-treat group, no patients had an objective response after 16 weeks. Eleven patients met the primary study endpoint with stable disease, 8 in the immune checkpoint inhibitors group and 3 in the non-immune checkpoint inhibitors group. Using the log-rank test, the p-value for the difference between groups was 0.008. In this study with off-label drugs, immune checkpoint inhibitors targeting TP53 mutations or PD-L1 expression were superior to the other drugs. This suggests the possibility of off-label use of anti-cancer drugs based on next-generation sequencing to be beneficial for advanced cancer patients without other therapeutic options.


2021 ◽  
Vol 30 (Sup12) ◽  
pp. S30-S36
Author(s):  
Harikrishna KR Nair ◽  
Nazni Wasi Ahmad ◽  
AA Ismail ◽  
Ali A Alabed ◽  
Benjamin Oh Zheming ◽  
...  

Objective: Maggot debridement therapy (MDT) has seen a resurgence in recent years in the treatment of hard-to-heal wounds, as a result of rising antibiotic resistance. The sterilised larvae of Lucilia cuprina have been used in MDT in Malaysia since 2003, with encouraging results for the treatment of hard-to-heal diabetic wounds. We report a case series of 30 patients selected from our clinic by convenient sampling with diabetic lower limb ulcers treated with MDT. The average age of patients receiving MDT was >50 years. Of the 30 patients in the study, nine were female and 21 were male. All patients had underlying diabetes, two patients had leg ulcers and 28 patients had diabetic foot ulcers. Sterilised Lucilia cuprina larvae were applied via a standard method of 10 maggots per square centimetre and dressed with sterile gauze. The study endpoint was defined as ≤5% coverage with slough or necrotic tissue following three successive applications of MDT. In this study, maximum debridement of wounds was achieved in 96.6% (29 patients) of our patients, with ≤5% coverage with slough or necrotic tissue, in addition to a reduction in wound-related pain, as assessed by a visual analogue scale. No adverse events were reported. The findings of this study support the use of MDT as a safe, efficacious, and cost-effective method of managing diabetic wounds.


BMC Medicine ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Chun-hui Dong ◽  
Chao-nan Gao ◽  
Xiao-hua An ◽  
Na Li ◽  
Le Yang ◽  
...  

Abstract Background Dexmedetomidine is a sedative agent that may have the potential to reduce the risk of post-intensive care syndrome (PICS). This study aimed to establish whether prophylactic nocturnal dexmedetomidine safely reduces postoperative PICS incidence and to develop an easy-to-use model for predicting the risk of PICS following cardiac surgery. Methods This was a single-center, double-blind, randomized, prospective, placebo-controlled trial. Patients undergoing cardiac surgery were randomly assigned (1:1) to dexmedetomidine or placebo (normal saline) groups between January 2019 and July 2020. Dexmedetomidine or a similar volume of saline was administered, with an infusion rate up to 1.2 μg/kg/h until the RASS remained between − 1 and 0. The primary study endpoint was PICS incidence at 6 months follow-up, as defined by cognitive, physical, or psychological impairments. Results We assessed 703 individuals for eligibility, of whom 508 were enrolled. Of these, there were 251 in the dexmedetomidine group and 257 in the placebo group that received the trial agent, forming a modified intention-to-treat population. PICS incidence at 6-month follow-up was significantly decreased in the dexmedetomidine group (54/251, 21.5%) relative to the placebo group (80/257, 31.1%) (odds ratio [OR] 0.793, 95% CI 0.665–0.945; p = 0.014). Psychological impairment was significantly reduced in the dexmedetomidine group relative to the placebo group (18.7% vs. 26.8%, OR 0.806, CI 0.672–0.967, p = 0.029). However, dexmedetomidine treatment was associated with a higher rate of hypotension. A nomogram revealed that age, education, a medical history of diabetes and smoking, dexmedetomidine treatment, postoperative atrial fibrillation, and sequential organ failure assessment scores at 8 h post-surgery were independent predictors of PICS. Conclusions Prophylactic nocturnal dexmedetomidine administration significantly reduced PICS incidence by a marked reduction in psychological impairment within a 6-month follow-up period. Trial registration ChiCTR, ChiCTR1800014314. Registered 5 January 2018, http://www.chictr.org.cn/index.aspx


Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
C. Le Gall-Ianotto ◽  
R. Verdet ◽  
E. Nowak ◽  
L. Le Roux ◽  
A. Gasse ◽  
...  

Abstract Background Aquagenic pruritus (AP), an intense sensation of scratching induced after water contact, is the most troublesome aspect of BCR-ABL1-negative myeloproliferative neoplasms (MPNs). Mostly described in polycythemia vera (PV, ~ 40%), it is also present in essential thrombocythemia (ET) and primary myelofibrosis (PMF) (10%). Even if this symptom can decrease or disappear under cytoreductive treatments, 30% of treated MPN patients still persist with a real impact on the quality of life (QoL). Because its pathophysiology is poorly understood, efficient symptomatic treatments of AP are missing. The neuropeptide substance P (SP) plays a crucial role in the induction of pruritus. Several studies showed the efficacy of aprepitant, an antagonist of SP receptor (NK-1R), in the treatment of chronic pruritus but never evaluated in AP. The objectives of APHYPAP are twofold: a clinical aim with the evaluation of the efficacy of two drugs in the treatment of a persistent AP for MPN patients and a biological aim to find clues to elucidate AP pathophysiology. Methods/design A multicentric, double-blind, double-placebo, randomized study will include 80 patients with MPN (PV or ET or PMF) treated since at least 6 months for their hemopathy but suffering from a persistent AP (VAS intensity ≥6/10). Patients will be randomized between aprepitant (80 mg daily) + placebo to match to hydroxyzine OR hydroxyzine (25 mg daily) + placebo to match to aprepitant for 14 days. At D0, baseline information will be collected and drugs dispense. Outcome measures will be assessed at D15, D30, D45, and D60. The primary study endpoint will be the reduction of pruritus intensity below (or equal) at 3/10 on VAS at D15. Secondary outcome measures will include the number of patients with a reduction or cessation of AP at D15 or D60; evaluation of QoL and AP characteristics at D0, D15, D30, D45, and D60 with MPN-SAF and AP questionnaires, respectively; modification of plasmatic concentrations of cytokines and neuropeptides at D0, D15, D30, and D60; and modification of epidermal innervation density and pruriceptor expression at D0 and D15. Discussion The APHYPAP trial will examine the efficacy of aprepitant vs hydroxyzine (reference treatment for AP) to treat persistent AP in MPN patients. The primary objective is to demonstrate the superiority of aprepitant vs hydroxyzine to treat persistent AP of MPN patients. The treatment received will be considered efficient if the AP intensity will be reduced at 3/10 or below on VAS after 14 days of treatment. The results of this study may provide a new treatment option for this troublesome symptom and also give us more insights in the pathophysiology understanding of AP. Trial registration APHYPAP. NCT03808805, first posted: January 18, 2019; last update posted: June 10, 2021. EudraCT 2018-090426-66


2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 689-690
Author(s):  
Philipp Gut ◽  
Giulia Lizzo ◽  
Eugenia Migliavacca ◽  
Leonidas Karagounis ◽  
Tim Heise ◽  
...  

Abstract Glutathione is an intracellular antioxidant that neutralizes reactive oxygen species and prevents tissue damage. Dietary supplementation with the glutathione precursors glycine and n-acetylcysteine supports the maintenance of normal glutathione levels in several age-related diseases, but the optimal doses and their efficacy in healthy elderly are not established. We report results from a randomized controlled clinical trial in 114 healthy volunteers (mean age = 65 years) receiving glycine and n-acetylcysteine (GlyNAC) at three different doses for two weeks (1.2g/1.2, 2.4g/2.4g, 3.6g/.3.6g of each amino acid). Older subjects showed increased oxidative damage and a lower reduced-to-oxidized glutathione ratio (GSH:GSSG) compared to young subjects, but unchanged total glutathione levels. GlyNAC did not increase levels of circulating glutathione compared to placebo treatment, the primary study endpoint. However, stratification analyses suggest that subjects with high oxidative stress and low glutathione status responded with glutathione generation. We find that unrelated to glutathione status, healthy aging was associated with lower levels of fasting glycine that can be increased towards those observed in young subjects with supplementation. Using preclinical models, we find that tissue glycine depletion is a common feature of healthy aging. Supplementation of old mice with glycine efficiently improved age-related decline of mitochondrial respiratory function in skeletal muscle and prevented a gene program associated with protein catabolism observed in control-treated animals. In conclusion, GlyNAC is safe and well-tolerated and may selectively increase glutathione levels in older subjects with oxidative stress and glutathione demand. Our data further suggest that glycine may support mitochondrial function independently of NAC.


2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Wenjian Ma ◽  
Side Gao ◽  
Sizhuang Huang ◽  
Jiansong Yuan ◽  
Mengyue Yu

Abstract Background Hyperuricemia (HUA) has been proved as a predictor of worse outcomes in patients with coronary artery disease. Here, we investigated the prognostic value of HUA in a distinct population with myocardial infarction with nonobstructive coronary arteries (MINOCA). Methods A total of 1179 MINOCA patients were enrolled and divided into HUA and non-HUA groups. HUA was defined as a serum uric acid level ≥ 420 μmol/L in men or ≥ 357 μmol/L in women. The primary study endpoint was a composite of major adverse cardiovascular events (MACE), including all-cause death, nonfatal MI, nonfatal stroke, revascularization, and hospitalization for unstable angina or heart failure. Kaplan–Meier, Cox regression, and receiver-operating characteristic analyses were performed. Results Patients with HUA (prevalence of 23.5%) had a significantly higher incidence of MACE (18.7% vs. 12.8%; p = 0.015) than patients without during the median follow-up of 41.7 months. HUA was closely associated with an increased risk of MACE even after multivariable adjustment (hazard ratio 1.498, 95% confidence interval: 1.080 to 2.077; p = 0.016). HUA remained a robust risk factor of MACE after propensity score matching analysis. Moreover, HUA showed an area under the curve (AUC) of 0.59 for predicting MACE. Incorporation of HUA to the thrombolysis in myocardial infarction (TIMI) score yielded a significant improvement in discrimination for MACE. Conclusions HUA was independently associated with poor prognosis after MINOCA. Routine assessment of HUA may facilitate risk stratification in this specific population.


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