A new class of highly potent NS5A inhibitors with an unsymmetric benzimidazole-difluorofluorene-imidazole core and distal [2.2.1]azabicyclic ring system was discovered. Optimization of antiviral potency and pharmacokinetics led to the identification of 39 (ledipasvir, GS-5885). Compound 39 (GT1a replicon EC50 = 31 pM) has an extended plasma half-life of 37-45 h in healthy volunteers and produces a rapid >3 log viral load reduction in monotherapy at oral doses of 3 mg or greater with once-daily dosing in genotype 1a HCV-infected patients. 39 has been shown to be safe and efficacious, with SVR12 rates up to 100% when used in combination with direct-acting antivirals having complementary mechanisms.

BackgroundWhole brain radiotherapy (WBRT) has been the treatment of choice for patients with brain metastases. However, change/decline of neurocognitive functions (NCFs) resulting from impaired hippocampal neurogenesis might occur after WBRT. It is reported that conformal hippocampal sparing would provide the preservation of NCFs. Our study aims to investigate the hippocampal dosimetry and to demonstrate the correlation between hippocampal dosimetry and neurocognitive outcomes in patients receiving hippocampal sparing during WBRT (HS-WBRT).MethodsForty prospectively recruited cancer patients underwent HS-WBRT for therapeutic or prophylactic purposes. Before receiving HS-WBRT, all participants received a battery of baseline neurocognitive assessment, including memory, executive functions and psychomotor speed. The follow-up neurocognitive assessment at 4 months after HS-WBRT was also performed. For the delivery of HS-WBRT, Volumetric Modulated Arc Therapy (VMAT) with two full arcs and two non-coplanar partial arcs was employed. For each treatment planning, dose volume histograms were generated for left hippocampus, right hippocampus, and the composite hippocampal structure respectively. Biologically equivalent doses in 2-Gy fractions (EQD2) assuming an alpha/beta ratio of 2 Gy were computed. To perform analyses addressing the correlation between hippocampal dosimetry and the change in scores of NCFs, pre- and post-HS-WBRT neurocognitive assessments were available in 24 patients in this study.ResultsScores of NCFs were quite stable before and after HS-WBRT in terms of hippocampus-dependent memory. Regarding verbal memory, the corresponding EQD2 values of 0, 10, 50, 80 % irradiating the composite hippocampal structure with <12.60 Gy, <8.81, <7.45 Gy and <5.83 Gy respectively were significantly associated with neurocognitive preservation indicated by the immediate recall of Word List Test of Wechsler Memory Scale-III. According to logistic regression analyses, it was noted that dosimetric parameters specific to left sided hippocampus exerted an influence on immediate recall of verbal memory (adjusted odds ratio, 4.08; p-value, 0.042, predicting patients’ neurocognitive decline after receiving HS-WBRT).ConclusionsFunctional preservation by hippocampal sparing during WBRT is indeed achieved in our study. Providing that modern VMAT techniques can reduce the dose irradiating bilateral hippocampi below dosimetric threshold, patients should be recruited in prospective trials of hippocampal sparing during cranial irradiation to accomplish neurocognitive preservation while maintaining intracranial control.Trial registrationCurrent Controlled Trials NCT02504788Electronic supplementary materialThe online version of this article (doi:10.1186/s13014-015-0562-x) contains supplementary material, which is available to authorized users.

The standard surgical treatment of hemorrhagic cerebral contusion is craniotomy with evacuation of the focal lesion. We assessed the safety and feasibility of performing decompressive craniectomy and duraplasty as the primary surgical intervention in this group of patients. Fifty-four consecutive patients with Glasgow Coma Scale (GCS) scores of less than or equal to 8, a frontal or temporal hemorrhagic contusion greater than 20 cm(3) in volume, and a midline shift of at least 5 mm or cisternal compression on computer tomography (CT) scan were studied. Sixteen (29.7%) underwent traditional craniotomy with hematoma evacuation, and 38 (70.4%) underwent craniectomy as the primary surgical treatment. Mortality, reoperation rate, Glasgow Outcome Scale-Extended (GOSE) scores, and length of stay in both the acute care and rehabilitation phase were compared between these two groups. Mortality (13.2% vs. 25.0%) and reoperation rate (7.9% vs. 37.5%) were lower in the craniectomy group, whereas the length of stay in both the acute care setting and the rehabilitation phase were similar between these two groups. The craniectomy group also had better GOSE score (5.55 vs. 3.56) at 6 months. Decompressive craniectomy is safe and effective as the primary surgical intervention for treatment of hemorrhagic contusion. This study also suggests that patient with hemorrhagic contusion can possibly have better outcome after craniectomy than other subgroup of patients with severe traumatic brain injury.

Neuropsychological impairments are not infrequent in children with moyamoya disease despite normal general intellectual functioning. The pattern of cognitive dysfunction is often associated with lesions in frontotemporal areas. Early detection and intervention shall be considered regarding cognitive outcome in pediatric group.