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Background: Futile recanalization (FR) is de fined as a poor 90-day outcome or lack of neurological improvement at 24 h despite successful recanalization in acute ischemic stroke (AIS) with large vessel occlusion (LVO) treated by mechanical throbectomy (MT). The No-reflow phenomenon (NRP) could be a possible cause of FR, but its evidence in AIS patients is scarce. Methods: We retrospectively analyzed 185 digital subtraction angiographies (DSA) of AIS patients with anterior circulation LVO after endovascular treatment. To better define NRP, we designed a score called the modified capillary index score (mCIS). The score is obtained by dividing the middle cerebral artery territory in three segments. For each segment, we gave 2 points if the capillary blush was present without any delay, 1 if delayed, and 0 if absent. The primary endpoint was to use mCIS to identify NRP on post-interventional DSA and to test whether this marker may predict FR and failure of early neurological improvement (fENI). The secondary endpoint was to search for a correlation between NRP, lesion volume, and hemorrhagic transformation. We used the ROC curve to define mCIS ≤ 3 as the cut-off and marker of NRP. Results: NRP was present in 35.1% of patients. NRP predicted fENI at 24 h (aOR 2.825, 95% CI 1.265–6.308, P = 0.011) and at 7 days (aOR 2.191, 95% CI 1.008–4.762, P = 0.048), but not 90-day FR. Moreover, NRP predicted hemorrhagic transformation (aOR 2.444, 95% CI 1.266–4.717, P = 0.008). Conclusions: The modified capillary index score (mCIS) seems useful in identifying NRP in AIS. In addition, mCIS was able to predict NRP that correlated with early clinical outcome and hemorrhagic transformation of the ischemic lesion. An external validation of the score is warranted. [ABSTRACT FROM AUTHOR]

Background: Heart failure (HF) is the second most important cardiac risk factor for stroke after atrial fibrillation (AF). Few data are available on mechanical thrombectomy (MT) in acute ischemic stroke (AIS) patients with HF. Methods: The source of data is the multicentre Italian Registry of Endovascular Treatment in Acute Stroke (IRETAS). All AIS patients ≥ 18 years receiving MT were categorised in two groups: HF and no-HF. Baseline clinical and neuroradiological findings on admission were analysed. Results: Of 8924 patients, 642 (7.2%) had HF. Compared to the no-HF group, HF patients had higher prevalence of cardiovascular risk factors. Rate of complete recanalisation (TICI 2b-3) was 76.9% in HF vs 78.1% in no-HF group (p = 0.481). Rate of symptomatic intracerebral haemorrhage at 24-h non-contrast computed tomography (NCCT) was 7.6% in HF vs 8.3% in no-HF patients (p = 0.520). At 3 months, 36.4% of HF patients and 48.2% of no-HF patients (p < 0.001) had mRS 0–2, and mortality was, respectively, 30.7% and 18.5% (p < 0.001). In multivariate logistic regression, HF was independently associated with mortality at 3 months (OR 1.53, 1.24–1.88 95% CI, p < 0.001). In multivariate ordinal regression, HF patients had a probability of transitioning to a higher mRS level of 1.23 (1.05–1.44 95% CI, p = 0.012). The propensity score analysis of two groups matched for age, sex, and NIHSS at admission yielded the same results. Conclusion: MT is safe and effective in HF patients with AIS. Patients with HF and AIS suffered from higher 3-month mortality and unfavourable outcome regardless of acute treatments. [ABSTRACT FROM AUTHOR]

The guanosine analog AT-527 represents a promising candidate against Severe Acute Respiratory Syndrome coronavirus type 2 (SARS-CoV-2). AT-527 recently entered phase III clinical trials for the treatment of COVID-19. Once in cells, AT-527 is converted into its triphosphate form, AT-9010, that presumably targets the viral RNA-dependent RNA polymerase (RdRp, nsp12), for incorporation into viral RNA. Here we report a 2.98 Å cryo-EM structure of the SARS-CoV-2 nsp12-nsp7-nsp82-RNA complex, showing AT-9010 bound at three sites of nsp12. In the RdRp active-site, one AT-9010 is incorporated at the 3′ end of the RNA product strand. Its modified ribose group (2′-fluoro, 2′-methyl) prevents correct alignment of the incoming NTP, in this case a second AT-9010, causing immediate termination of RNA synthesis. The third AT-9010 is bound to the N-terminal domain of nsp12 - known as the NiRAN. In contrast to native NTPs, AT-9010 is in a flipped orientation in the active-site, with its guanine base unexpectedly occupying a previously unnoticed cavity. AT-9010 outcompetes all native nucleotides for NiRAN binding, inhibiting its nucleotidyltransferase activity. The dual mechanism of action of AT-527 at both RdRp and NiRAN active sites represents a promising research avenue against COVID-19. The drug AT-527 targets the SARS-CoV-2 replication machinery. Here the authors use Cryo-EM to show how AT-527 inhibits SARS-CoV-2 polymerase by acting as an immediate RNA chain terminator and stably binding in a NiRAN active-site pocket; impeding an essential nucleotide-transfer activity. [ABSTRACT FROM AUTHOR]

Environmental managers require a sensitive and reliable means to prove, with the highest level of confidence possible, where non-native fish species exist and where they do not. Therefore, a nested PCR (nPCR) protocol was developed to detect the environmental DNA (eDNA) of a case-study species, topmouth gudgeon Pseudorasbora parva, which was recently the subject of a national eradication campaign in the UK. The nPCR protocol was tested in the laboratory and in the field in a series of coordinated surveys (eDNA and conventional sampling with traps) at a commercial angling venue in southern England where an initial eDNA survey, based on conventional PCR (cPCR), found P. parva to be present in one of the seven ponds. In the laboratory, the nPCR protocol was on average 100× more sensitive than cPCR, providing a 100% detection rate at DNA concentrations of 3 × 10−8 ng/µL (8 DNA copies per µL). In the field, nPCR and conventional trapping both detected P. parva in only one of the seven angling ponds, the same infested pond as in the previous cPCR-based study. Following eradication work on the infested pond, no eDNA of P. parva was detected using nPCR in either the formerly-infested pond or the adjacent pond, which had been used to quarantine large commercially-valuable fishes. In management applications where the veracity of negative results may be of equal importance as confirmation of positive detections, nPCR protocols provide a useful addition to the analytical toolkit available to inform decision makers responsible for non-native species management. [ABSTRACT FROM AUTHOR]

Background: A better understanding of the molecular profile of anal squamous cell carcinomas (ASCCs) is necessary to consider new therapeutic approaches, and the identification of prognostic and predictive factors for response to treatment.Methods: We retrospectively analysed tumours from ASCC patients for mutational analysis of KRAS, NRAS, HRAS, BRAF, PIK3CA, MET, TP53 and FBXW7 genes by HRM and Sanger sequencing analysis.Results: Specimens from 148 patients were analysed: 96 treatment-naive tumours and 52 recurrences after initial radiotherapy (RT) or chemoradiotherapy (CRT). Mutations of KRAS, PIK3CA, FBXW7 and TP53 genes were present in 3 (2.0%), 30 (20.3%), 9 (6.1%) and 7 tumours (4.7%), respectively. The distribution of the mutations was similar between treatment-naive tumours and recurrences, except for TP53 mutations being more frequent in recurrences (P=0.0005). In patients treated with abdominoperineal resection (APR) after relapse (n=38, median follow-up of 18.2 years), overall survival (OS) was significantly correlated with HPV16 status (P=0.048), gender (P=0.045) and PIK3CA mutation (P=0.037). The PIK3CA status retained its prognostic significance in Cox multivariate regression analysis (P=0.025).Conclusions: Our study identified PIK3CA mutation as an independent prognostic factor in patients who underwent APR for ASCC recurrence, suggesting a potential benefit from adjuvant treatment and the evaluation of targeted therapies with PI3K/Akt/mTor inhibitors in PIK3CA-mutated patients. [ABSTRACT FROM AUTHOR]

Providing high level tools for parallel programming while sustaining a high level of performance has been a challenge that techniques like Domain Specific Embedded Languages try to solve. In previous works, we investigated the design of such a DSEL-NT $$^2$$ -providing a Matlab -like syntax for parallel numerical computations inside a C++ library. In this paper, we show how NT $$^2\!$$ has been redesigned for shared memory systems in an extensible and portable way. The new NT $$^2\!$$ design relies on a tiered Parallel Skeleton system built using asynchronous task management and automatic compile-time taskification of user level code. We describe how this system can operate various shared memory runtimes and evaluate the design by using two benchmarks implementing linear algebra algorithms. [ABSTRACT FROM AUTHOR]

Use of parametric statistical models can be a solution to reduce the follow-up period time required to estimate long-term survival. Mould and Boag were the first to use the lognormal model. Competing risks methodology seems more suitable when a particular event type is of interest than classical survival analysis. The objective was to evaluate the ability of the Jeong and Fine model to predict long-term cumulative incidence. Survival data recorded by Institut Curie (Paris) from 4761 breast cancer patients treated and followed between 1981 and 2013 were used. Long-term cumulative incidence rates predicted by the model using short-term follow-up data were compared to non-parametric estimation using complete follow-up data. 20- or 25-year cumulative incidence rates for loco-regional recurrence and distant metastasis predicted by the model using a maximum of 10 years of follow-up data had a maximum difference of around 6 % compared to non-parametric estimation. Prediction rates were underestimated for the third and composite event (contralateral or second cancer or death). Predictive ability of Jeong and Fine model on breast cancer data was generally good considering the short follow-up period time used for the estimation especially when a proportion of patient did not experience loco-regional recurrence or distant metastasis. [ABSTRACT FROM AUTHOR]

Biological Sequence Comparison is an important operation in Bioinformatics that is often used to relate organisms. Smith and Waterman proposed an exact algorithm that compares two sequences in quadratic time and space. Due to high computing power and memory requirements, SW is usually executed on High Performance Computing (HPC) platforms such as multicore clusters and CellBEs. Since HPC architectures exhibit very different hardware characteristics, porting an application to them is an error-prone time-consuming task. BSP++ is an implementation of BSP that aims to facilitate parallel programming, reducing the effort to port code. In this paper, we propose and evaluate a parallel BSP++ strategy to execute SW on multiple multicore and manycore platforms. Given the same base code, we generated MPI, OpenMP, MPI/OpenMP, CellBE and MPI/CellBE versions, which were executed on heterogeneous platforms with up to 6,144 cores. The results obtained with real DNA sequences show that the performance of our versions is comparable to the hand-tuned strategies in the literature, evidencing the appropriateness and flexibility of our approach. [ABSTRACT FROM AUTHOR]

Description of the various modalities of breast and ovarian cancer risk management, patient choices and their outcome in a single-center cohort of 158 unaffected women carrying a BRCA1 or BRCA2 germline mutation. Between 1998 and 2009, 158 unaffected women carrying a BRCA1 or BRCA2 gene mutation were prospectively followed. The following variables were studied: general and gynecological characteristics, data concerning any prophylactic procedures, and data concerning the outcome of these patients. Median age at inclusion was 37 years and median follow-up was 54 months. Among the 156 women who received systematic information about prophylactic mastectomy, 5.3 % decided to undergo surgery within 36 months after disclosure of genetic results. Prophylactic salpingo-oophorectomy was performed in 68 women. Among women in whom follow-up started between the ages of 40 and 50 years, prophylactic salpingo-oophorectomy was performed, within 24 months after start of follow-up, in 83.7 and 52 % of women with BRCA1 and BRCA2 mutations, respectively. Twenty four women developed breast cancer. Ovarian cancer was detected during prophylactic salpingo-oophorectomy in two women (2.9 %). In this cohort of French women carrying BRCA1/ 2 mutations, prophylactic mastectomy was a rarely used option. However, good compliance with prophylactic salpingo-oophorectomy was observed. This study confirms the high breast cancer risk in these women. [ABSTRACT FROM AUTHOR]

Axillary lymph node dissection (ALND) for patients with positive sentinel lymph nodes (SLNs) is currently under discussion in the literature. The breast cancer nomogram (BCN), an online tool developed by the Memorial Sloan-Kettering Cancer Center (MSKCC), aims to predict the risk of positive non-SLN in SLN-positive patients. The purpose of this study was to test the accuracy of the nomogram on patients with macrometastatic and micrometastatic SLN-positive biopsy findings. Patient characteristics, tumor pathology, and positive SLN characteristics were collected on 588 consecutive patients who underwent completion ALND. The MSKCC BCN tool was used to calculate risk of metastases for all 588 cases that included a subgroup of the 213 patients with SLN micrometastases. The BCN was performed for positive SLN biopsy findings regardless of the method of metastasis detection. Evaluation of the BCN was performed by the area under the curve method. The BCN applied to all 588 patients achieved an area under the receiver operating characteristic curve (ROC) of .724 (range, .677–.771) compared with .76 in the MSKCC study. When the tool was applied solely to micrometastases found by hematoxylin and eosin staining and metastases found by immunohistochemistry, the area under the ROC was .538 (range, .423–.653). The MSKCC nomogram has been validated for all the patients having a metastatic SLN at the Institut Curie. However, this model was not reliably predictive for positive non–SLN in cases with micrometastic positive SLN. [ABSTRACT FROM AUTHOR]

This study is an analysis of the criteria considered when prescribing concomitant chemotherapy and radiotherapy, as a routine treatment for patients with anal canal cancer, and related complications. Between 1990 and 1996, 67 patients were treated at Institut Curie for invasive, nonmetastatic cancer of the anal canal. Median age was 65 years (range, 35-90 years). TNM stage distribution was as follows: seven T1, 17 T2, 27 T3, 16 T4, and 22 N+ patients. A total of 29 patients (i.e., five T1/T2, and 24 T3/T4) received concurrent chemotherapy and radiotherapy. Radiotherapy volumes and dose and prescribed dose for chemotherapy were not statistically different from one group of patients to another. Only 55% of T3/T4 patients underwent standard chemoradiation treatment for anal canal cancer. Age was the one of main factor in determining if the patient would undergo concomitant chemotherapy or not. For the T3/T4 patients, concomitant chemotherapy was prescribed to 69% of patients <55 years, 90% of patients between 56 and 64 years, 45% of patients between 65 and 75 years, and 20% of patients over 75 years (P<0.02).Overall survival at 4 years was 66%. The 4 years overall survival rate of T3/T4 patients, who underwent concomitant chemotherapy, was 72%, and that of T3/T4 patient who did not, was 34% (P<0.04). The patients who did not undergo chemotherapy were significantly older. The difference in cause-specific survival rates (72 vs 48%) was not significant. Relapse-free interval without local recurrence at 4 years was 70%. Relapse-free interval of T3/T4 patients was 78% with chemotherapy and 60% without chemotherapy (p=NS). Rates of treatment discontinuation and early toxicity were not statistically different. Late complications occurred in 33 patients, eight of whom had grade 2/3 tumours. At 2 years, complications occurred in 39% of patients who had undergone concomitant chemotherapy, and in 20% of patients who had not (p<0.02). Differences in grade 2/3 complications were not significant. In conclusion, although radiotherapy with concomitant chemotherapy is considered the current ‘gold-standard’ treatment for anal canal cancer, in our daily experience, only 55% of our T3/T4 patients have undergone this treatment. The remainder did not undergo chemotherapy mainly because they were deemed too old. In this series, no increase in local control and cause-specific survival was observed in patients who received concomitant chemotherapy; this may be due to the small number of patients included in the series. The increased rate of late complications observed in patients who received the combined treatment, however, provides evidence that this treatment should be restricted to younger patients without comorbidity and therefore justifies our position. Perhaps reduction of doses of chemotherapy must be discussed for older patients.British Journal of Cancer (2003) 89, 2057-2061. doi:10.1038/sj.bjc.6601378 www.bjcancer.com [ABSTRACT FROM AUTHOR]

Organic light-emitting diodes (OLEDs) show promise for applications as high-quality self-emissive displays for portable devices such as cellular phones and personal organizers. Although monochrome operation is sufficient for some applications, the extension to multi-colour devices—such as RGB (red, green, blue) matrix displays—could greatly enhance their technological impact. Multi-colour OLEDs have been successfully fabricated by vacuum deposition of small electroluminescent molecules, but solution processing of larger molecules (electroluminescent polymers) would result in a cheaper and simpler manufacturing process. However, it has proved difficult to combine the solution processing approach with the high-resolution patterning techniques required to produce a pixelated display. Recent attempts have focused on the modification of standard printing techniques, such as screen printing and ink jetting, but those still have technical drawbacks. Here we report a class of electroluminescent polymers that can be patterned in a way similar to standard photoresist materials—soluble polymers with oxetane sidegroups that can be crosslinked photochemically to produce insoluble polymer networks in desired areas. The resolution of the process is sufficient to fabricate pixelated matrix displays. Consecutive deposition of polymers that are luminescent in each of the three RGB colours yielded a device with efficiencies comparable to state-of-the-art OLEDs and even slightly reduced onset voltages. [ABSTRACT FROM AUTHOR]

Background: The objectives of this study were, first, to define the preoperative criteria for using solely the blue dye method and, second, to decrease its operator dependence in predicting axillary lymph node status. Methods: Two hundred fifty-three women consecutively identified with operable breast cancer underwent sentinel lymph node (SLN) detection by the patent blue dye method followed by completion axillary lymph node dissection. A standard pathological examination was performed for all SLN. Then, a pathological color quality assessment (PCQA), which checked for the presence of the blue dye, was performed on the paraffin blocks of the nonmetastatic SLN. Six preoperative identifiable variables likely to influence the detection rate were examined. Results: The surgical detection (sd) rate was 84% (213 of 253) and the PCQA rate was 73% (185 of 253). Only breast size (sd, P = .0005; PCQA, P = .0007) and body mass index ≤30 (sd, P = .005; PCQA, P = .0007) were significant for SLN identification. Multivariate analysis revealed two independent factors influencing SLN identification: breast size (sd, P = .0001; PCQA, P = .002) and the timing of injection—injection prior to lumpectomy (sd, P =.04). Conclusions: The optimal patient features for identifying the SLN by the patent blue dye method are small or medium-sized breasts, low body fat, and that the procedure is carried out prior to tumor excision. The PCQA offers a useful second assessment of the surgically removed SLN, introducing an independent element of quality control. [ABSTRACT FROM AUTHOR]

Stroke is the third leading cause of death, after cardiac disease and cancer, in most industrialised countries. Moreover, stroke is an important cause of long term disability and is the most common life-threatening neurological disease. During past years, there has been a declining trend in stroke incidence, mortality and case-fatality; the reasons for this are unclear and there is no evidence of the persistence of this favourable trend since 1980. The improved knowledge and, consequently, improved management of stroke risk factors and new trends in acute stroke treatment seem to account for this evolution. We present a review of stroke epidemiology, aetiology and emergency clinical and diagnostic aspects, paying particular attention to ischaemic strokes, which have been the subject of most of the research and clinical trials carried out in recent years. Moreover, we propose a brief guideline for diagnosis of stroke in the acute phase. [ABSTRACT FROM AUTHOR]

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