Safety and optimal neuroprotection of neu2000 in acute ischemic stroke with reCanalization: study protocol for a randomized, double-blinded, placebo-controlled, phase-II trial

BACKGROUND: The potential of neuroprotective agents should be revisited in the era of endovascular thrombectomy (EVT) for acute large-artery occlusion because their preclinical effects have been optimized for ischemia and reperfusion injury. Neu2000, a derivative of sulfasalazine, is a multi-target neuroprotectant. It selectively blocks N-methyl-D-aspartate receptors and scavenges for free radicals. This trial aimed to determine whether neuroprotectant administration before EVT is safe and leads to a more favorable outcome. METHODS: This trial is a phase-II, multicenter, three-arm, randomized, double-blinded, placebo-controlled, blinded-endpoint drug trial that enrolled participants aged ≥ 19 years undergoing an EVT attempt less than 8 h from symptom onset, with baseline National Institutes of Health Stroke Scale (NIHSS) score ≥ 8, Alberta Stroke Program Early CT score ≥ 6, evidence of large-artery occlusion, and at least moderate collaterals on computed tomography angiography. EVT-attempted patients are randomized into control, low-dose (2.75 g), and high-dose (5.25 g) Neu2000KWL over 5 days. Seventy participants per group are enrolled for 90% power, assuming that the treatment group has a 28.4% higher proportion of participants with functional independence than the placebo group. The primary outcome, based on intention-to-treat criteria is the improvement of modified Rankin Scale (mRS) scores at 3 months using a dichotomized model. Safety outcomes include symptomatic intracranial hemorrhage within 5 days. Secondary outcomes are distributional change of mRS, mean differences in NIHSS score, proportion of NIHSS score 0-2, and Barthel Index > 90 at 1 and 4 weeks, and 3 months. DISCUSSION: The trial results may provide information on new therapeutic options as multi-target neuroprotection might mitigate reperfusion injury in patients with acute ischemic stroke before EVT

PHF7 Modulates BRDT Stability and Histone-to-Protamine Exchange during Spermiogenesis

Chang Rok Kim, Taichi Noda, Hyunkyung Kim, Gibeom Kim, Seongwan Park, Yongwoo Na, Seiya Oura, Keisuke Shimada, Injin Bang, Jun-Yeong Ahn, Yong Ryoul Kim, Se Kyu Oh, Hee-Jung Choi, Jong-Seo Kim, Inkyung Jung, Ho Lee, Yuki Okada, Masahito Ikawa, Sung Hee Baek, PHF7 Modulates BRDT Stability and Histone-to-Protamine Exchange during Spermiogenesis, Cell Reports, Volume 32, Issue 4, 2020, 107950, ISSN 2211-1247, https://doi.org/10.1016/j.celrep.2020.107950

Baseline characteristics of the Korean genetic cohort of inherited cystic kidney disease

Background Identifying genetic mutations in individuals with inherited cystic kidney disease is necessary for precise treatment. We aimed to elucidate the genetic characteristics of cystic kidney disease in the Korean population. Methods We conducted a 3-year prospective, multicenter cohort study at eight hospitals from May 2019 to May 2022. Patients with more than three renal cysts were enrolled and classified into two categories, typical autosomal dominant polycystic kidney disease (ADPKD) and atypical PKD. We identified the clinical characteristics and performed a genetic analysis using a targeted gene panel. Results A total of 725 adult patients were included in the study, of which 560 (77.2%) were diagnosed with typical ADPKD and 165 (22.8%) had atypical PKD. Among the typical ADPKD cases, the Mayo imaging classification was as follows: 1A (55, 9.9%), 1B (149, 26.6%), 1C (198, 35.8%), 1D (90, 16.3%), and 1E (61, 11.0%). The atypical PKD cases were classified as bilateral cystic with bilateral atrophic (31, 37.3%), lopsided (27, 32.5%), unilateral (nine, 10.8%), segmental (eight, 9.6%), bilateral cystic with unilateral atrophic (seven, 8.4%), and asymmetric (one, 1.2%). Pathogenic variants were found in 64.3% of the patients using the ciliopathy-related targeted gene panel. The typical ADPKD group demonstrated a higher discovery rate (62.3%) than the atypical PKD group (41.8%). Conclusion We present a nationwide genetic cohort’s baseline clinical and genetic characteristics for Korean cystic kidney disease

Reversibly controlled ternary polar states and ferroelectric bias promoted by boosting square???tensile???strain

Interaction between dipoles often emerges intriguing physical phenomena, such as exchange bias in the magnetic heterostructures and magnetoelectric effect in multiferroics, which lead to advances in multifunctional heterostructures. However, the defect-dipole tends to be considered the undesired to deteriorate the electronic functionality. Here, we report deterministic switching between the ferroelectric and the pinched states by exploiting a new substrate of cubic perovskite, BaZrO3, which boosts square-tensile-strain to BaTiO3 and promotes four-variants in-plane spontaneous polarization with oxygen vacancy creation. First-principles calculations propose a complex of an oxygen vacancy and two Ti3+ ions coins a charge-neutral defect-dipole. Cooperative control of the defect-dipole and the spontaneous polarization reveals ternary in-plane polar states characterized by biased/pinched hysteresis loops. Furthermore, we experimentally demonstrate that three electrically controlled polar-ordering states lead to switchable and non-volatile dielectric states for application of non-destructive electro-dielectric memory. This discovery opens a new route to develop functional materials via manipulating defect-dipoles and offers a novel platform to advance heteroepitaxy beyond the prevalent perovskite substrates

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Microbial and physicochemical monitoring of granular sludge during start-up of thermophilic UASB reactor

Mesophilically-grown granular sludge seeded in thermophilic UASB reactor was monitored to better understand the start-up process of the reactor. The reactor was fed with a synthetic wastewater containing glucose. As COD loading rate increased stepwise, methane production rate increased. Maximum values of COD removal efficiency (95%) and methane production rate (5.3 l/day) were achieved by approximately day-80 and remained constant afterward. However, physicochemical and microbial properties of granules kept changing even after day-80. Specific methanogenic activity (SMA) was initially negligible, and increased continuously until day-153 and remained constant afterward, showing the maximum value of 1.51+/-0.13 g CH4-COD/g VSS/day. Deteriorated settling ability of granules recovered the initial value by day-98 and was maintained afterward, as determined by sludge volume index. Initially reduced granule size increased until day-126, reaching a plateau of 1.1 rum. Combined use of fluorescence in situ hybridization and confocal laser scanning microscopy (CLSM) allowed to localize families of Methanosaetaceae and Methanosarcinaceae in granules with time. Quantitative analyses of CLSM images of granule sections showed abundance patterns of the methanogens and numerical dominance of Methanosaeta spp. throughout the start-up period. The trend of SMA agreed well with abundance patterns of the methanogens

Long-term result of direct frontalis sling with fascia lata in congenital ptosis

Background : : Congenital ptosis with poor levator function are very difficult to make good results of functional and cosmetic side. Surgical methods for the correction of congenital ptosis with poor levator function, including frontalis suspension or maximal levator resection, remain controversial. We evaluated the postoperative surgical and cosmetic long-term outcomes after frontalis sling operation with preserved fascia lata for congenital ptosis with poor levator function. Objective: To evaluate the long-term outcome of asymmetric ptosis with frontalis sling operation preserved fascia lata by modified direct tarsal fixation in congenital ptosis patients. Methods : : A retrospective case series was performed. From January 2000 to December 2018, 53 patients (30 unilateral and 23 bilateral asymmetric ptosis) with 70 eyelids who underwent frontalis sling with preserved fascia lata were included. Six patients underwent levator resection at opposite eye. The surgical results were graded as excellent, good and poor. Results : : The mean age at the time of surgery was 5.2±3.2 years (range, 1-43 years) with a mean follow-up time of 106.6±29.1 months (range, 60-196 months). Satisfactory results (excellent or good result) were obtained in 94.2% of the patients. Patients were divided into two groups based on levator function as follows: 0 to 2 mm (24 cases) and 2.5 to 4.0 mm (46 cases). Preoperative levator function, margin reflex distance-1 and levator dehiscence were not correlated with postoperative surgical outcomes. Complications were exposure keratopathy (8.6%), lidcrease asymmetry (7.1%), overcorrection (5.7%), entropion (5.7%), and eyelash ptosis (2.9%). Conclusion : : Frontalis sling operation by preserved fascia lata with modified direct tarsal fixation is a simple but effective treatment for severe congenital ptosis with poor levator function. And it has good long-term results