Journal articles on the topic '616-78'

Abstract Hereditary hearing loss is a monogenic disease with high genetic heterogeneity. Variants in more than 100 deafness genes underlie the basis of its pathogenesis. The aim of this study was to assess the ratio of SNVs in known deafness genes contributing to the etiology of both sporadic and familial sensorineural hearing loss patients from China. DNA samples from 1127 individuals, including normal hearing controls (n = 616), sporadic SNHL patients (n = 433), and deaf individuals (n = 78) from 30 hearing loss pedigrees were collected. The NGS tests included analysis of sequence alterations in 129 genes. The variants were interpreted according to the ACMG/AMP guidelines for genetic hearing loss combined with NGS data from 616 ethnically matched normal hearing adult controls. We identified a positive molecular diagnosis in 226 patients with sporadic SNHL (52.19%) and in patients from 17 deafness pedigrees (56.67%). Ethnically matched MAF filtering reduced the variants of unknown significance by 8.7%, from 6216 to 5675. Some complexities that may restrict causative variant identification are discussed. This report highlight the clinical utility of NGS panels identifying disease-causing variants for the diagnosis of hearing loss and underlines the importance of a broad data of control and ACMG/AMP standards for accurate clinical delineation of VUS variants.

The area of New South Wales infested with Cassinia aiwuta (sifton bush) increased from 93 000 ha in 1975 to 616 000 ha in 1988, indicating a need to investigate its biology and control. Of 6 samples of seed collected over 3 years from 2 sites, 5 germinated readily, emerged from a soil depth of 15 mm or less, and grew 7-48 times slower than pasture species in 28 days. The remaining sample had an after-ripening period of more than 5 months before full germination was achieved. Lime depressed growth of C. arcuata seedlings whilst superphosphate promoted growth. Preemergence herbicides simazine and atrazine killed seedlings in the cotyledon stage, while post-emergence herbicides glyphosate, triclopyr + picloram and hexazinone killed 40-, 78- and 139-day-old seedlings. Control on arable land could be achieved by burying seeds below 15 mm, followed by cultivation or herbicide application to remove establishing seedlings and addition of lime and spelling to allow sown species to smother late-establishing seedlings. On non-arable land burning to remove mature plants, spraying to kill establishing seedlings and aerial application of seed of improved species and superphosphate will contribute to control on soils that can support sown species without the application of large quantities of lime.

This study evaluates the costs and utilities of different treatment strategies for stable chronic obstructive pulmonary disease (COPD) patients based on Markov model and provides guidance for clinical decision and health policy making. Patients with stable COPD from four subcenters had been investigated. A Markov model with three states, namely, GOLD 1-2, GOLD 3-4, and death, was built using TreeAge Pro 2011 software. Cost-utility ratio (CUR) and incremental cost-utility ratio (ICUR) from forty Markov circles were applied to measuring the economics evaluation of three different treatments. A total of 236 stable COPD patients were randomly assigned into three groups, Western medicine group (79 cases), traditional Chinese medicine (TCM) group (79 cases), and combined group (78 cases). The results of Markov cohort simulation showed that the accumulative quality-adjusted life years (QALYs) of the three above groups per 100 000 people in 40 years were 1 702 773, 1 616 797, and 1 709 668 years, respectively, and the accumulative costs were 13 582 138 466, 1 207 904 113, and 14 656 607 371 Yuan, respectively. The CURs of the three groups were 87 235, 74 602, and 87 223 Yuan/QALY, respectively. ICURs of combined group were 8 707 and 41 705 Yuan as against Western medicine group and TCM group, respectively. Therefore, combined treatment has a lower cost, higher health output, and more socioeconomic benefits in the long run. Markov model is recommended to conduct health economics evaluation of different treatments for COPD.

Mammalian mitochondrial DNA often contains a short DNA displacement loop at the heavy-strand origin of replication. This short nascent DNA molecule has been used to study site-specific termination of mitochondrial DNA synthesis in human and mouse cells. We examined D-loop strand termination in two distantly related artiodactyls, the pig and the cow. Porcine mitochondrial DNA was unique among mammals in that it contained only a single species of D-loop single-stranded DNA. Its 3' end mapped to a site 187 nucleotides from the 5' end of the proline tRNA gene. This site was 21 and 47 nucleotides 5' to two very similar sequences (5' ACATATPyATTAT 3') which are closely related to the human and mouse termination-associated sequences noted by Doda et al. (J. N. Doda, D. T. Wright, and D. A. Clayton, Proc. Nat. Acad. Sci. USA 78:616-6120, 1981). Bovine mitochondrial DNA contained three major D-loop DNA species whose 3' ends mapped to three different sites. These sites were not found in the porcine sequence. However, the bovine termination sites were located 60 to 64 base pairs 5' from sequences which were also very similar to the termination-associated sequences present in pigs and other mammals. These results firmly establish the concept that arrest of heavy-strand DNA synthesis is an event determined, at least in part, by template sequence. They also suggest that arrest is determined by sequences which are a considerable physical distance away from the actual termination site.

Mammalian mitochondrial DNA often contains a short DNA displacement loop at the heavy-strand origin of replication. This short nascent DNA molecule has been used to study site-specific termination of mitochondrial DNA synthesis in human and mouse cells. We examined D-loop strand termination in two distantly related artiodactyls, the pig and the cow. Porcine mitochondrial DNA was unique among mammals in that it contained only a single species of D-loop single-stranded DNA. Its 3' end mapped to a site 187 nucleotides from the 5' end of the proline tRNA gene. This site was 21 and 47 nucleotides 5' to two very similar sequences (5' ACATATPyATTAT 3') which are closely related to the human and mouse termination-associated sequences noted by Doda et al. (J. N. Doda, D. T. Wright, and D. A. Clayton, Proc. Nat. Acad. Sci. USA 78:616-6120, 1981). Bovine mitochondrial DNA contained three major D-loop DNA species whose 3' ends mapped to three different sites. These sites were not found in the porcine sequence. However, the bovine termination sites were located 60 to 64 base pairs 5' from sequences which were also very similar to the termination-associated sequences present in pigs and other mammals. These results firmly establish the concept that arrest of heavy-strand DNA synthesis is an event determined, at least in part, by template sequence. They also suggest that arrest is determined by sequences which are a considerable physical distance away from the actual termination site.

10545 Background: Early identification of survivors at high risk for treatment-induced cardiomyopathy may allow for prevention and/or early intervention. We utilized deep learning methods using COG guideline-recommended baseline electrocardiography (ECG) to improve prediction of future cardiomyopathy. Methods: SJLIFE is a cohort of 5-year clinically assessed childhood cancer survivors including baseline ECG measurements. Development of cardiomyopathy was identified from clinical and echocardiographic measurement using CTCAE criteria (grade 3-4). We applied deep learning approaches to ECG, treatment exposure and demographic data obtained at baseline SJLIFE assessment. We trained a cascaded model combining a 12-layer 1D convolutional neural network to extract features from waveform ECG signals with a 2-layer dense neural network to embed features from other phenotypic data in tabular format to determine if use of deep learning with ECG data could improve prediction of cardiomyopathy. Results: Among 1,218 subjects (median age 31.7 years, range 18.4-66.4) without cardiomyopathy at baseline evaluation, 616 (51%) were male, 1,041 (85%) white, 157 (13%) African American and 792 (65%) were survivors of lymphoma/leukemia. Follow-up averaged 5 (0.5 to 9) years from baseline examination. Mean chest radiation dose was 1350 cGy (range 0 to 6,200 cGy) and mean cumulative anthracycline dose was 191 mg/m2 (range o to 734 mg/m2). A total of 114 (9.4%) survivors developed cardiomyopathy after baseline. A cascaded deep learning model built on a training set (N = 974 participants) classified cardiomyopathy in the test set (N = 244 participants) using both clinical and ECG data with a sensitivity of 70%, specificity of 73%, and AUC of 0.74 (95% CI 0.63-0.85), compared to a model using clinical data alone (sensitivity 61%, specificity 62%, and AUC 0.67, 95% CI 0.56-0.79). In subgroup analyses, models predicting cardiomyopathy within 0-4 years following baseline had a sensitivity, specificity, and AUC of 77%, 78%, and 0.78 (0.65-0.91), respectively. When predicting cardiomyopathy 5-9 years following baseline, model performance dropped to a sensitivity, specificity, and AUC of 70%, 70%, and 0.68 (0.50-0.87), respectively. Conclusions: Deep learning using ECG at baseline evaluation significantly improved prediction of cardiomyopathy in childhood cancer survivors at high risk for cardiomyopathy. Future directions will incorporate deep learning approaches to echocardiography to further improve prediction.

7578 Background: In early-stage NSCLC the neoadjuvant approach is a promising option since relatively low compliance rate with adjuvant therapy and incomplete recovery after surgery are commonly reported. The NATCH trial was therefore designed to address whether neoadjuvant or adjuvant paclitaxel (P)/carboplatin (C) improves disease-free survival compared to surgery alone in early-stage NSCLC. Patients randomized to the neoadjuvant arm have now undergone analyses of toxicity, radiographic response, resectability and surgical mortality. Methods: Consenting patients with clinical stage I (>2 cm), II, T3N1 NSCLC are randomized to surgery alone or 3 cycles of neoadjuvant PC (P: 200 mg/m2/ C:AUC=6 on day 1 every 3wk), or surgery followed by 3 cycles of adjuvant PC at the same schedule. Planned sample size of this prospective, randomized trial is 628 patients. Results: Since 2000, 616 patients have been accrued, 200 in the neoadjuvant arm, 208 in the adjuvant arm, and 208 in the surgery arm. Demographic data is now available for 162 patients in the neoadjuvant arm: 89% male; median age 64 years (range, 37–78); 45% PS 0; 53% squamous cell, 27% adenocarcinoma, 13% large cell; 7% stage IA, 64% IB, 2% IIA, 24% IIB, 2.5% T3N1. Neoadjuvant chemotherapy has been well tolerated with a median number of cycles per patient of 3. No unexpected toxicities have been seen with 12% of patients having grade 3–4 neutropenia and 43% grade 1–2 anemia. Major radiographic response has been observed in 59% of patients and progression during chemotherapy occurred in 6%. No patient characteristics were predictive for clinical response. Resection procedures at thoracotomy: lobectomy or bilobectomy in 70%, pneumonectomy in 26%, and explorative thoracotomy due to unresectable disease in 3% of patients. Post-operative mortality was 4%. Median tumor size was 4.5 cm at baseline CT-scan and 2.5 cm at surgery. At surgery, 9% patients had pathologic complete response, 75% N0–1 disease (with persistent T tumor), and 15% pathologic N2 disease. Conclusion: Neoadjuvant chemotherapy in early NSCLC has proven feasible and safe in this large multicenter sample. Chemotherapy compliance has been high and resectability rates as expected. Our findings are comparable with those of previous studies (BLOT and S9900). Mature survival results of the NATCH trial are expected in 2009. No significant financial relationships to disclose.

Abstract Background: Flow cytometry (FCM) has recently been recognized as an important supplementary tool in the diagnostic work-up of patients with MDS. Within the international MDS-flow working group of the ELN, different and also novel Flow scores have been evaluated and tested in rather small patients series. Aim: Currently available FCM scores have been prospectively compared concerning their potential diagnostic and prognostic impact in patients with proven or suspected MDS. Patients and Methods: Bone marrow (BM) samples from 616 patients (951 measurements) with proven or suspected MDS, 42 MPN patients, 30/18 MDS patients in cytomorphologic/cytogenetic CR, 22 patients with inappropriate BM aspirations as well as 48 age matched controls have been analyzed by FCM. For measurement and analysis a FACS-CantoII cytometer including FACS-DiVa software was used, performing an 8-color panel and measuring 200,000 events per sample. The following FCM scores were compared: FCSS (granulopoiesis / monopoiesis), Ogata-score (blasts), ELN-red score and Mathis score (both erythropoiesis), and the new iFScore (granulo-, mono-, erythropoiesis, and blasts). Overall survival (OS) was estimated with a median follow up of 21 month (range: 3.4-77 month) applying the Log-Rank-Test within SPSS software. Results: The new iFScore, evaluating granulo-, mono-, erythropoiesis and blasts, turned out to be the most comprehensive score with the best balance between sensitivity and specificity (81%; 78%). FCSS indeed showed a comparably high sensitivity (82%) but has a clearly lower specificity (60%). The Ogata-score and the red-scores showed a lower sensitivity (60%, 31%, 40%) but were very specific (92%, 97%, 89%). Interestingly, despite inappropriate bone marrow aspirations (w/o crumbs) in 22 patients the new iFScore accounted for a "MDS conformable" result in 72% of these cases. Next, the prognostic impact of the different FCM scores was evaluated. Of note, patients with MDS conformable FCM-scores showed a significantly shorter OS compared to patients with scores being not MDS conformable, new iFS, Ogata- and Mathis-score: p = 0.001 (ELN-red: p = 0.003; FCSS: p = 0.005). This also held true evaluating only untreated patients, with Ogata-score exhibiting the highest significance (p < 0.001). Remarkably, even when analyzing the subgroup of MDS-SLD/MLD with normal karyotype and without ringsideroblasts plus non-clonal cytopenias only, a high Ogata score predicted for a significantly lower OS (p = 0.035; median OS = 40 month vs. not reached). Thus, the group of patients with MDS conformable FCM showed significantly higher IPSS-R (p = 0.023) and more mutations (p = 0.0357). When evaluating MDS patients in cytomorphologic or even cytogenetic CR, 23% (17%) showed a MDS conformable iFS with significantly shorter OS (p = 0.025; p = 0.026). Finally, 49% or 35% of patients with MPN showed MDS conformable iFS or Ogata scores, respectively. This translated in a shorter OS in those patients (p = 0.048; p = 0.018). Conclusions: Currently available FCM scores have different sensitivity and specificity in diagnosing MDS, with the novel and comprehensive iFScore, capturing granulo-, mono-, erythropoiesis and blasts together, being superior to other FCM-scores. Additionally, iFS and Ogata score comprise significant prognostic information, even in lower risk MDS. Remarkably, FCM might be a tool to refine response evaluation in MDS and reveal significant dyspoietic features in a subset of MPN patients. Disclosures Platzbecker: Celgene: Research Funding.

AbstractEffects of mammalian herbivory and seasonal drought were studied for Virola surinamensis (Myristicaceae) juveniles on Barro Colorado Island, Panama. Seedlings were planted at three months of age and the juveniles were monitored for two years; Treatments included: intact plants protected from mammals by cages, defoliated plants similarly protected, and unprotected plants, each planted in treefall gaps, on gap edges, and in the shaded understorey.Juveniles planted in treefall gaps survived seasonal drought far better than those planted on gap edges or in shaded understorey. Two years after establishment, juveniles protected from mammalian herbivory showed a 78% survival in gaps (mean 6.8% skylight), 50% survival on gap edges (mean 3.0% skylight), and 33% survival in shaded understorey (1.4% skylight). This advantage was due to accelerated growth in gaps. Juveniles in gaps increased 616% in height, 1075% in leaf number, and 1800% in total leaf area. Comparable numbers in edges were 247%, 378% and 690%; in understorey 33%, 222% and 289%. Accelerated growth in gaps permitted yearlings to survive drought that killed suppressed yearlings in understorey. Mean light differentials as small as 0.6% and 0.3% skylight significantly influenced survival on edges and in shaded understorey, respectively.Mammalian herbivory killed juveniles directly, and defoliation by mammals strongly accentuated drought mortality by suppressing root development. Natural defoliation was not attributable to gap conditions. Demographic projections from experimental data suggest that mammalian herbivory kills at least 48% of the juveniles of this species over two years, and contributes to the death of 32% more that actually die of drought stress. These projections suggest that 14% of the juveniles of this species die of drought mortality, independent of herbivory, during the first two years. Herbivory most strongly affects plants < 0.5 m in height, and is a continuing source of mortality among suppressed juveniles in the understorey. Steep slopes and large seed size each enhanced juvenile growth and survival in the intermediate conditions of gap edges, but not under the extreme conditions of gaps or shaded understorey.The context of establishment determines the ‘shade tolerance’ of this conspicuous canopy tree. Without serious mammalian herbivory or extreme dry seasons, V. surinamensis can easily recruit as a shade tolerant plant in the understorey. Under present conditions on Barro Colorado Island, it cannot. Persistence involves both the chances of arrival in different microhabitats, and survival therein. Projections that include both the forest area represented by gaps, gap edges, and understorey and the experimental results from this study indicate that juvenile V. surinamensis can survive for two years in gaps, edges, and understorey, but that the higher proportions of vigorous individuals survive in edges, gaps and understorey, respectively.

Abstract Introduction: Insulin like growth factor (IGF-2) mediated hypoglycemia secondary to solitary fibrous tumor (SFT), also known as Doege-Potter syndrome is a rare paraneoplastic syndrome. The tumor cells produce large amounts of high molecular weight IGF 2 precursor protein called “big IGF-2” which binds to insulin and IGF receptors in liver, muscle and other peripheral tissues. This causes reduced gluconeogenesis and increased uptake of glucose by the muscle and other tissues leading to hypoglycemia. Big IGF-2 also exerts central negative feedback of growth hormone causing reduction of IGF-I production. Most SFTs are benign and localized (approximately 78-88%). As a result, tumor excision alone would often lead to resolution of the hypoglycemia. We present a case of metastatic SFT with multiple metastasis managed with oral prednisone. Clinical Case: A 44-year-old man with metastatic SFT presented with bilateral humeral fractures. He has known metastatic disease to the brain, lung, liver, bony lytic lesions over a course of eleven years. It has progressed despite multiple chemotherapy and radiation therapies. Prior to admission, he had multiple syncopal episodes associated with fasting hypoglycemia. He reported capillary blood glucose values ranging between 30-50 mg/dl during these episodes which would improve after drinking juice or eating candy. There was no history of diabetes mellitus or use of oral hypoglycemic agents or insulin. On admission, he had a capillary blood glucose value of less than 20 mg/dl, which was confirmed by a serum glucose value of 18 mg/dl on basic metabolic panel. His renal, liver and thyroid function tests were normal. Significant labs include: serum glucose 17 mg/dl, C-peptide &lt;0.10 ng/ml (n: 1-4 ng/ml), serum insulin &lt;1.6 Uu/ml (n: &lt;20 Uu/ml), beta-hydroxybutyrate &lt;0.2 mmol/L (n: &lt;0.3), cortisol 10.8 ug/dl(n: 5-15 ug/dl) glucagon 6 pg/ml(ref 8-57 pg/ml), insulin-like growth factor-1 (IGF 1) 20 ng/ml (n: 52-328), and IGF-2 level 380 ng/ml (267-616 ng/ml), improvement in blood glucose from 46 to 111 mg/dl after 1-gram glucagon administration. The IGF-2/IGF-1 ratio of 19 confirmed our clinical suspicion of non-islet cell tumor hypoglycemia (NICTH). He was started on prednisone 20 mg twice daily with marked improvement in hypoglycemia. Conclusion: NICTH is a rare cause of hypoglycemia and should be considered in the differential while evaluating hypoglycemia in malignancy. For diagnosing NICTH, assays for big IGF-II are not commercially available. However, the IGF-II:IGF-I ratio is considered to be a surrogate marker of big IGFII concentration. The normal ratio is 3 and ratio &gt;10 is diagnostic of NICTH. In cases like ours where tumor resection is not possible, glucocorticoids are most effective in management of hypoglycemia by inhibiting big IGF2 production and stimulating gluconeogenesis.

Tổng quan: phẫu thuật tim cho bệnh nhân đang mang thai mang lại nhiều rủi ro cho cả mẹ và thai nhi. Chúng tôi trình bày kinh nghiệm điều trị phẫu thuật ở bệnh nhân có bệnh van tim đang mang thai. Phương pháp nghiên cứu: hồi cứu các trường hợp BN có bệnh van tim đang mang thai được trong giai đoạn 1998-2018 tại Viện Tim thành phố Hồ Chí Minh. Loại trừ nhóm bệnh cơ tim chu sản, bệnh tim bẩm sinh. Kết quả: tổng số BN là 78 bao gồm 15 BN được phẫu thuật nong van tim kín, 63 BN được tạo hình hoặc thay van. Không có tử vong ở nhóm nong van tim kín, tử vong mẹ ở nhóm BN điều trị phẫu thuật tim hở: 3 (4,7%). Biến chứng tim mạch chính: 16 (20,5%) bao gồm suy tim nặng, rối loạn nhịp tim và phù phổi cấp. Các yếu tố làm tăng tử vong mẹ là phân độ NYHA trước mổ (p= 0,037) và mổ cấp cứu (p= 0,034). Tử vong thai nhi là 10 (13,1%). Biến chứng sản khoa: 28 (36,8%) bao gồm phải mổ lấy thai, sẩy thai, dọa sẩy thai và sinh sớm. Các yếu tố làm tăng tử vong thai nhi là thời gian tuần hoàn hoàn cơ thể (p= 0,003) và thời gian kẹp động mạch chủ (p= 0,01). Thời gian theo dõi trung bình là 104,25 ± 68,7 tháng (từ 12- 238 tháng). Kết luận: điều trị chuyên biệt cho nhóm bệnh này vẫn còn là thách thức, có nhiều biến chứng. Cần sự phối hợp của nhiều chuyên khoa sâu, tối ưu hóa tuần hoàn ngoài cơ thể và chọn thời điểm phẫu thuật phù hợp nhằm mang lại kết quả tốt cho cả mẹ và con.

BACKGROUND Liver cirrhosis (LC) is the final common pathway for all chronic liver diseases. It is a major cause of morbidity and mortality in adults globally. Systemic inflammation has now been proposed to play a crucial role in the natural history of progressive liver damage and is one of the main causes of precipitating compensated liver cirrhosis to decompensated state. Neutrophil to lymphocyte ratio (NLR) has been considered as an important inexpensive biomarker to indicate ongoing inflammation in patients with cirrhosis. The purpose of this study was to find out if there is any significant correlation between neutrophil to lymphocyte ratio and Child Turcotte Pugh score (CTP) among liver cirrhosis patients. METHODS We conducted a cross sectional study involving patients diagnosed with liver cirrhosis in Fakhruddin Ali Ahmed Medical College & Hospital, Barpeta, from November 2019 to January 2021. All patients were diagnosed based on clinical history, examination and ultrasound. The study enrolled 101 cirrhotic patients irrespective of aetiology. Total white blood cell (WBC) count, neutrophil count and lymphocyte count were recorded and neutrophil to lymphocyte count was calculated. Child Turcotte Pugh score was calculated by taking data from medical records of the patients. RESULTS Out of the 101 patients enrolled in our study, majority were males (78). A significant correlation was found between NLR and CTP score in liver cirrhosis patients. The patients with NLR < 3 showed mean CTP score of 6.1 ± 0.55, with NLR in between 3 to 6 showed CTP score of 8.2 ± 1.2 and with NLR > 6 showed mean CTP score of 11 ± 0.76 CONCLUSIONS NLR can be used as a single independent biomarker and a simpler scoring system for assessment of severity of liver cirrhosis but needs further studies and evaluation. KEYWORDS Neutrophil-to-Lymphocyte Ratio, Child-Turcotte-Pugh Score, Cirrhosis

IntroductionIn the Phase 3 ORACLE-MS trial in 616 subjects with a first demyelinating event at high risk of converting to multiple sclerosis (MS), treatment with cladribine tablets 10 mg (3.5 mg/kg or 5.25 mg/kg cumulative dose over 2 years [CT3.5 and CT5.25, respectively]) significantly delayed time to conversion to clinically definite multiple sclerosis (CDMS) according to Poser criteria (67% or 62% risk reduction [RR], respectively) and time to conversion to 2005 McDonald MS (50% or 57% RR, respectively), versus placebo. The objective was to analyze the effect of cladribine tablets vs placebo on converstion to CDMS and McDonald MS across ORACLE-MS patient subgroups based on baseline characteristics.MethodsIn this post-hoc analysis, time-to-conversion to CDMS or McDonald MS over the double-blind period was analyzed for patients treated with CT5.25 (N=204), CT3.5 (N=206) or placebo (N=206) across different subgroups. Subgroups were defined by baseline characteristics which have been investigated as potential predictors of CDMS conversion (age [<30 or ≥30 years], gender, first classification demyelinating event [monofocal or multifocal], presence of T1 Gd+ lesions and number of T2 lesions [<9 or ≥9]).ResultsTreatment with CT3.5 or CT5.25 was consistently efficacious across the subgroups examined on conversion to CDMS versus placebo for most comparisons (RR range: CT3.5, 39%–72%; CT5.25, 36%–79%). Similarly, treatment effect of both doses on conversion to 2005 McDonald MS was consistent across subgroups (CT3.5,40%–59%;CT5.25,42%–79%).ConclusionsThe effect of cladribine tablets on delaying the time-to-conversion to CDMS, or to McDonald MS, is consistent across subgroups.

Introduction. Evaluation of the influence level of the pre-organized cracks in tensile zone of the reinforced concrete beams on their crack resistance, deformability under long-term loading is investigated in the article.Materials and methods. Concrete for specimen was produced in laboratory and factory on portland cement of the 500-grade at W/C=0,71; concrete composition 1:1,9:4 (by weight); strength of cube at 28th days – 13,85 MPa; strength of prism with dimensions 10/10*40 cm – 11,48 MPa; span calculation – 78 cm; steel rebar grade – A400 with diameter of 10 mm. Organized crack was formed by installing plate with thickness of 0,5 mm and height of 30 mm on the rebar in the zone of maximum moments.Results. The experiments confirmed the hypothesis about the beams rigidity with pre-organized cracks in comparison with stochastic cracks under the influence of long-term loading. As a result, the beams with pre-organized cracks provide the smaller deflection after long-term period than the beams without organized cracks. Thus, the proposed method of the deflections calculation of the reinforced concrete beams with pre-organized cracks under the long-term loading helps to reduce deflection to 33%.Discussion and conclusion. The findings of this study suggest that the presence of pre-organized cracks reduces the beams deflections in comparison with the specimens of section, and such method actually regulates the stress-strain state of reinforced concrete structures and leads to the smooth deformation at all stages under the influence of long-term loading.

Introduction: Daratumumab (DARA) is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. The addition of DARA to standard-of-care regimens in phase 3 studies reduced the risk of disease progression or death by ≥44%, nearly doubled the rate of complete response or better, and induced a ≥3-fold increase in minimal residual disease (MRD)-negativity rates versus standard of care alone in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) and relapsed/refractory multiple myeloma. In the primary analysis of the phase 3 ALCYONE study (median follow-up: 16.5 months), a significant progression-free survival (PFS) benefit (median not reached vs 18.1 months; hazard ratio [HR], 0.50; P &lt;0.001) was observed with the addition of DARA to bortezomib/melphalan/prednisone (D-VMP) in patients with transplant-ineligible NDMM, without an increase in overall toxicity (Mateos MV, et al. N Engl J Med. 2018;378[6]:518-528). D-VMP continued to demonstrate a significant PFS benefit versus VMP alone after 1 year of additional follow-up, including in patients ≥75 years of age (Dimopoulos MA, et al. Blood. 2018;132[Suppl 1]:156). After a median follow-up of 27.8 months, D-VMP reduced the risk of disease progression or death by 57% versus VMP alone, with a 24-month PFS rate of 63% in the D-VMP group and 36% in the VMP group. This PFS benefit was observed regardless of patient age and was maintained during the subsequent line of therapy in patients with transplant-ineligible NDMM. Here, we present &gt;36 months of follow-up from ALCYONE, including analysis of overall survival (OS) from a prespecified interim analysis. Methods: Patients with NDMM ineligible for high-dose chemotherapy and autologous stem cell transplantation due to age (≥65 years) or comorbidities were randomized 1:1 to receive up to nine 6-week cycles of VMP (bortezomib 1.3 mg/m2 subcutaneously on Days 1, 4, 8, 11, 22, 25, 29, and 32 of Cycle 1 and Days 1, 8, 22, and 29 of Cycles 2-9; melphalan 9 mg/m2 orally and prednisone 60 mg/m2 orally on Days 1-4 of Cycles 1-9) with or without DARA (16 mg/kg intravenously once weekly for Cycle 1, once every 3 weeks for Cycles 2-9, and once every 4 weeks for Cycles 10+ until disease progression). The primary endpoint was PFS. Secondary endpoints included overall response rate, rate of complete response or better, rate of very good partial response or better, MRD-negativity rate (10-5 threshold), PFS on subsequent line of therapy (PFS2), OS, and safety. Results: A total of 706 patients were enrolled in this study (D-VMP: n = 350; VMP: n = 356). Patient baseline characteristics were well balanced between treatment arms. The median (range) age was 71 (40-93) years, and 29.9% of patients were ≥75 years of age. 518 (84.1%) and 98 (15.9%) of 616 patients evaluated had standard and high (del17p, t[14;16], and/or t[4;14] positive) cytogenetic risk, respectively, as assessed via local fluorescence in-situ hybridization/karyotyping. Median PFS was 36.4 months with D-VMP versus 19.3 months with VMP after a median follow-up of 40.08 months (HR, 0.42; 95% confidence interval [CI], 0.34-0.51; P &lt;0.0001; Figure A). Median PFS2 was not reached with D-VMP versus 42.3 months with VMP (HR, 0.55; 95% CI, 0.43-0.71; P &lt;0.0001). The estimated 36-month OS rate was 78% with D-VMP versus 68% with VMP, with a significant benefit for OS observed for D-VMP versus VMP alone (HR, 0.60; 95% CI, 0.46-0.80; P = 0.0003; Figure B); median OS was not reached in either group and follow-up is ongoing. Additional efficacy data, including MRD negativity, and updated safety data will be presented at the meeting. Conclusions: For the first time, we demonstrate that the addition of DARA to VMP prolongs OS in patients with transplant-ineligible NDMM, with a 40% reduction in the risk of death versus VMP alone after a median follow-up of 40 months. D-VMP continued to demonstrate a significant PFS benefit, which was also maintained during the subsequent line of therapy. These findings, together with the phase 3 MAIA study (DARA plus lenalidomide/dexamethasone vs lenalidomide/dexamethasone), continue to support the addition of DARA to frontline treatment regimens in patients with transplant-ineligible NDMM. Disclosures Mateos: Abbvie: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; EDO: Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria. Cavo:Janssen, Celgene, Amgen, Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Amgen, BMS, Abbvie, Takeda: Honoraria; Janssen, Celgene: Other: Travel Accommodations; Janssen, Celgene: Speakers Bureau. Bladé:Irctures: Honoraria; Janssen, Celgene, Amgen, Takeda: Membership on an entity's Board of Directors or advisory committees. Dimopoulos:Sanofi Oncology: Research Funding. Suzuki:Ono: Research Funding; BMS: Honoraria, Research Funding; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Jakubowiak:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; KaryoPharm Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Juno: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkyLineDx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Knop:Janssen, AMGEN, Bristol-Myers Squibb, Celgene: Consultancy, Honoraria. Lucio:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Nagy:Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Cook:Celgene, Jannsen-Cilag, Takeda: Honoraria, Research Funding; Amgen, Bristol-Myers Squibb, GlycoMimetics, Seattle Genetics and Sanofi: Honoraria. Liberati:Janssen: Honoraria; Bristol & Mayer: Honoraria; Celgene: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy. Campbell:Janssen: Honoraria, Research Funding, Speakers Bureau. Garg:Novartis, Janssen: Research Funding; Janssen, Takeda, Novartis: Other: Travel expenses; Janssen: Honoraria. Krevvata:Janssen: Employment. Wang:Janssen: Employment. Kudva:Janssen: Employment, Equity Ownership. Ukropec:Janssen: Employment, Equity Ownership. Wroblewski:Janssen: Employment, Equity Ownership. Kobos:Janssen: Employment. San-Miguel:Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria.

Introdução: O número crescente de infecções causadas por fungos e o surgimento de microrganismos resistentes tem sinalizado a necessidade da busca por novos agentes antifúngicos, fomentando a pesquisa em moléculas promissoras, como os O-glicosídeos. Objetivo: Partindo dessa premissa, objetivamos a síntese e investigação da atividade antifúngica do benzil 2,3-didesoxi-α-D-eritro-hex-2-enopiranosídeo isolado e quando associado com a anfotericina B. Material e métodos: Inicialmente foi sintetizado o benzil 4,6-di-O-acetil-2,3-didesoxi-α-D-eritro-hex-2-enopiranosídeo a partir da reação entre o 3,4,6-tri-O-acetil-D-glucal e álcool benzílico via catálise ácida e irradiação ultrassônica seguida por sua hidrólise em meio básico para levar ao benzil 2,3-didesoxi-α-D-eritro-hex-2-enopiranosídeo. Este foi submetido à avaliação antifúngica por meio do método da microdiluição em caldo e estudo da associação com a anfotericina B pelo método de Checkerboard. Resultados: O benzil 4,6-di-O-acetil-2,3-didesoxi-α-D-eritro-hex-2-enopiranosídeo e o benzil 2,3-didesoxi-α-D-eritro-hex-2-enopiranosídeo foram obtidos em excelentes rendimentos 91 e 94 %, respectivamente. O benzil 2,3-didesoxi-α-D-eritro-hex-2-enopiranosídeo apresentou atividade antifúngica apenas contra as cepas de Candida albicans ATCC 76615, Candida albicans ATCC 76485 e Candida guilliermondiiLM 103, e sua associação com a anfotericina B foi classificada como indiferente. Conclusão: Estes resultados possibilitam futuros estudos envolvendo esta classe de moléculas, avaliação dos possíveis mecanismos de ação e avaliar outras atividades biológicas, uma vez que esta classe molecular sustenta a expectativa de baixa toxicidade, devido ao seu padrão de biocompatibilidade. Descritores: Síntese Química; Metabolismo dos Carboidratos; Fungos; Candida. Referências Silva S, Negri M, Henriques M, Oliveira R, Williams DW, Azeredo J. 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Study of petrological and geochemical characteristics of mantle peridotite xenoliths in Pliocene alkaline basalt in Nghia Dan (West Nghe An) was carried out. Rock-forming clinopyroxenes, the major trace element containers, were separated from the xenoliths to analyze for major, trace element and Sr-Nd isotopic compositions. The data were interpreted for source geochemical characteristics and geodynamic processes of the lithospheric mantle beneath the region. The peridotite xenoliths being mostly spinel-lherzolites in composition, are residual entities having been produced following partial melting events of ultramafic rocks in the asthenosphere. They are depleted in trace element abundance and Sr-Nd isotopic composition. Some are even more depleted as compared to mid-ocean ridge mantle xenoliths. Modelled calculation based on trace element abundances and their corresponding solid/liquid distribution coefficients showed that the Nghia Dan mantle xenoliths may be produced of melting degrees from 8 to 12%. Applying various methods for two-pyroxene temperature- pressure estimates, the Nghia Dan mantle xenoliths show ranges of crystallization temperature and pressure, respectively, of 1010-1044°C and 13-14.2 kbar, roughly about 43km. A geotherm constructed for the mantle xenoliths showed a higher geothermal gradient as compared to that of in the western Highlands (Vietnam) and a conductive model, implying a thermal perturbation under the region. The calculated Sm-Nd model ages for the clinopyroxenes yielded 127 and 122 Ma. 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Abstract Background Prospective review and feedback (PRF) of antibiotic prescriptions and compulsory computerized decision support system (CDSS) are 2 strategies of antimicrobial stewardship. There are limited studies investigating their combined effects. We hypothesized that the use of on-demand (voluntary) CDSS would achieve similar patient outcomes compared with automatically triggered (compulsory) CDSS whenever broad-spectrum antibiotics are ordered. Methods A parallel-group, 1:1 block cluster randomized crossover study was conducted in 32 medical and surgical wards from March to August 2017. CDSS use for piperacillin-tazobactam or carbapenem in the intervention clusters was at the demand of the doctor, while in the control clusters CDSS use was compulsory. PRF was continued for both arms. The primary outcome was 30-day mortality. Results Six hundred forty-one and 616 patients were randomized to voluntary and compulsory CDSS, respectively. There were no differences in 30-day mortality (hazard ratio [HR], 0.87; 95% CI, 0.67–1.12), re-infection and re-admission rates, antibiotic duration, length of stay, or hospitalization cost. The proportion of patients receiving PRF recommendations was not significantly lower in the voluntary CDSS arm (62 [10%] vs 81 [13%]; P = .05). Appropriate indication of antibiotics was high in both arms (351/448 [78%] vs 330/433 [74%]; P = .18). However, in geriatric medicine patients where antibiotic appropriateness was &lt;50%, prescription via compulsory CDSS resulted in a shorter length of stay and lower hospitalization cost. Conclusions Voluntary broad-spectrum antibiotics with PRF via CDSS did not result in differing clinical outcomes, antibiotic duration, or length of stay. However, in the setting of low antibiotic appropriateness, compulsory CDSS may be beneficial.

Potassium (K) is the essential element for plant growth. It is one of the critical factors that determine crop yield, quality, and especially leaf development in tobacco. However, the molecular mechanism of potassium use efficiency (KUE), especially non-coding RNA, is still unknown. In this study, tobacco seedlings were employed, and their hydro-cultivation with K treatments of low and sufficient concentrations was engaged. Physiological analysis showed that low potassium treatment could promote malondialdehyde (MDA) accumulation and antioxidant enzyme activities such as peroxidase (POD), ascorbate-peroxidase (APX). After transcriptomic analysis, a total of 10,585 LncRNA transcripts were identified, and 242 of them were significantly differently expressed under potassium starvation. Furthermore, co-expression networks were constructed and generated 78 potential regulation modules in which coding gene and LncRNAs are involved and functional jointly. By further module-trait analysis and module membership (MM) ranking, nine modules, including 616 coding RNAs and 146 LncRNAs, showed a high correlation with K treatments, and 20 hub K-responsive LncRNAs were finally predicted. Following gene ontology (GO) analysis, the results showed potassium starvation inducing the pathway of antioxidative stress which is consistent with the physiology result mentioned above. Simultaneously, a part of detected LncRNAs, such as MSTRG.6626.1, MSTRG.11330.1, and MSTRG.16041.1, were co-relating with a bench of MYB, C3H, and NFYC transcript factors in response to the stress. Overall, this research provided a set of LncRNAs that respond to K concentration from starvation and sufficient supply. Simultaneously, the regulation network and potential co-functioning genes were listed as well. This massive dataset would serve as an outstanding clue for further study in tobacco and other plant species for nutrient physiology and molecular regulation mechanism.

Abstract Background The scale of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among health care workers (HCWs), particularly in resource-limited settings, remains unclear. To address this concern, universal (non-symptom-based) screening of HCWs was piloted to determine the proportion of SARS-CoV-2 infection and the associated epidemiological and clinical risk factors at a large public health care facility in Egypt. Methods Baseline voluntary screening of 4040 HCWs took place between 22 April and 14 May 2020 at 12 hospitals and medical centres in Cairo. Epidemiological and clinical data were collected using an online survey. All participants were tested for SARS-CoV-2 using reverse transcription polymerase chain reaction (RT-PCR) and rapid IgM and IgG serological tests. Results Of the 4040 HCWs screened, 170 [4.2%; 95% confidence interval (CI): 3.6-4.9] tested positive for SARS-CoV-2 by either of the three tests (i.e. infected); 125/170 (73.5%) tested PCR-positive. Most infected HCWs were nurses (97/170, 57.5%). Median age of infected HCWs was 31.5 [interquartile range (IQR): 27.0–41.3] years. Of infected HCWs, 78 (45.9%) reported contact with a suspected case and 47 (27.6%) reported face-to-face contact within 2 m with a confirmed case. The proportion of infection among symptomatic HCWs (n = 54/616) was 8.8% (95% CI: 6.7-11.3); 6/54 (11.1%) had fever ≥38°C and 7/54 (13.0%) reported severe symptoms. Most infected HCWs were asymptomatic (116/170, 68.2%). The proportion of infection among asymptomatic HCWs (n = 116/3424) was 3.4% (95% CI: 2.8-4.0). Conclusions The high rate of asymptomatic infections among HCWs reinforces the need for expanding universal regular testing. The infection rate among symptomatic HCWs in this study is comparable with the national rate detected through symptom-based testing. This suggests that infections among HCWs may reflect community rather than nosocomial transmission during the early phase of the COVID-19 epidemic in Egypt.

Background: Age-related comorbidities prone older adults to polypharmacy and to an increased risk of potentially inappropriate medication (PIM) use. This work aims to analyze the concordance and overlap among the EU(7)-PIM list, 2019 Beers criteria, and Screening Tool of Older Person’s Prescriptions (STOPP) version 2 criteria and also to analyze the prevalence of PIM.Methods: A retrospective cohort study was conducted on older inpatients of an internal medicine ward. Demographic, clinical, and pharmacological data were collected, during March 2020. After PIM identification by the EU(7)-PIM list, Beers criteria, and STOPP v2 criteria, the concordance and overlap between criteria were analyzed. A descriptive analysis was performed, and all the results with a p-value lower than 0.05 were considered statistically significant.Results: A total of 616 older patients were included in the study whose median age was 85 (Q1–Q3) (78–89) years. Most of the older patients were male (51.6%), and the median (Q1–Q3) number of days of hospitalization was 17 (13–22) days. According to the EU(7)-PIM list, Beers criteria, and STOPP criteria, 79.7, 92.0, and 76.5% of older adults, respectively, used at least one PIM. A poor concordance (&lt;63.4%) among criteria was observed. An association between PIM and the number of prescribed medicines was found in all applied criteria. Moreover, an association between the number of PIMs and diagnoses of endocrine, nutritional, and metabolic diseases, mental, behavioral, and neurodevelopmental disorders, and circulatory system diseases and days of hospitalization was observed according to Beers criteria, and that with diseases of the circulatory system and musculoskeletal system and connective tissue was observed according to STOPP criteria.Conclusion: Despite the poor concordance between the EU(7)-PIM list, 2019 Beers, and STOPP v2 criteria, this work highlights the need for more studies in inpatients to develop strategies to facilitate the identification of PIM to decrease the high prevalence of PIM in hospitalized patients. The poor concordance among criteria also highlights the need to develop new tools adapting the existing criteria to medical ward inpatients.

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Permaculture is a creative design process that is based on ethics and design principles. It guides us to mimic the patterns and relationships we can find in nature and can be applied to all aspects of human habitation, from agriculture to ecological building, from appropriate technology to education and even economics. (permacultureprinciples.com)This paper considers permaculture as an example of counterculture in Australia. Permaculture is a neologism, the result of a contraction of ‘permanent’ and ‘agriculture’. In accordance with David Holmgren and Richard Telford definition quoted above, we intend permaculture as a design process based on a set of ethical and design principles. Rather than describing the history of permaculture, we choose two moments as paradigmatic of its evolution in relation to counterculture.The first moment is permaculture’s beginnings steeped in the same late 1960s turbulence that saw some people pursue an alternative lifestyle in Northern NSW and a rural idyll in Tasmania (Grayson and Payne). Ideas of a return to the land circulating in this first moment coalesced around the publication in 1978 of the book Permaculture One: A Perennial Agriculture for Human Settlements by Bill Mollison and David Holmgren, which functioned as “a disruptive technology, an idea that threatened to disrupt business as usual, to change the way we thought and did things”, as Russ Grayson writes in his contextual history of permaculture. The second moment is best exemplified by the definitions of permaculture as “a holistic system of design … most often applied to basic human needs such as water, food and shelter … also used to design more abstract systems such as community and economic structures” (Milkwood) and as “also a world wide network and movement of individuals and groups working in both rich and poor countries on all continents” (Holmgren).We argue that the shift in understanding of permaculture from the “back to the land movement” (Grayson) as a more wholesome alternative to consumer society to the contemporary conceptualisation of permaculture as an assemblage and global network of practices, is representative of the shifting dynamic between dominant paradigms and counterculture from the 1970s to the present. While counterculture was a useful way to understand the agency of subcultures (i.e. by countering mainstream culture and society) contemporary forms of globalised capitalism demand different models and vocabularies within which the idea of “counter” as clear cut alternative becomes an awkward fit.On the contrary we see the emergence of a repertoire of practices aimed at small-scale, localised solutions connected in transnational networks (Pink 105). These practices operate contrapuntally, a concept we borrow from Edward Said’s Culture and Imperialism (1993), to define how divergent practices play off each other while remaining at the edge, but still in a relation of interdependence with a dominant paradigm. In Said’s terms “contrapuntal reading” reveals what is left at the periphery of a mainstream narrative, but is at the same time instrumental to the development of events in the narrative itself. To illustrate this concept Said makes the case of novels where colonial plantations at the edge of the Empire make possible a certain lifestyle in England, but don’t appear in the narrative of that lifestyle itself (66-67).In keeping with permaculture design ecological principles, we argue that today permaculture is best understood as part of an assemblage of design objects, bacteria, economies, humans, plants, technologies, actions, theories, mushrooms, policies, affects, desires, animals, business, material and immaterial labour and politics and that it can be read as contrapuntal rather than as oppositional practice. Contrapuntal insofar as it is not directly oppositional preferring to reframe and reorientate everyday practices. The paper is structured in three parts: in the first one we frame our argument by providing a background to our understanding of counterculture and assemblage; in the second we introduce the beginning of permaculture in its historical context, and in third we propose to consider permaculture as an assemblage.Background: Counterculture and Assemblage We do not have the scope in this article to engage with contested definitions of counterculture in the Australian context, or their relation to contraculture or subculture. There is an emerging literature (Stickells, Robinson) touched on elsewhere in this issue. In this paper we view counterculture as social movements that “undermine societal hierarchies which structure urban life and create, instead a city organised on the basis of values such as action, local cultures, and decentred, participatory democracy” (Castells 19-20). Our focus on cities demonstrates the ways counterculture has shifted away from oppositional protest and towards ways of living sustainably in an increasingly urbanised world.Permaculture resonates with Castells’s definition and with other forms of protest, or what Musgrove calls “the dialectics of utopia” (16), a dynamic tension of political activism (resistance) and personal growth (aesthetics and play) that characterised ‘counterculture’ in the 1970s. McKay offers a similar view when he says such acts of counterculture are capable of “both a utopian gesture and a practical display of resistance” (27). But as a design practice, permaculture goes beyond the spectacle of protest.In this sense permaculture can be understood as an everyday act of resistance: “The design act is not a boycott, strike, protest, demonstration, or some other political act, but lends its power of resistance from being precisely a designerly way of intervening into people’s lives” (Markussen 38). We view permaculture design as a form of design activism that is embedded in everyday life. It is a process that aims to reorient a practice not by disrupting it but by becoming part of it.Guy Julier cites permaculture, along with the appropriate technology movement and community architecture, as one of many examples of radical thinking in design that emerged in the 1970s (225). This alignment of permaculture as a design practice that is connected to counterculture in an assemblage, but not entirely defined by it, is important in understanding the endurance of permaculture as a form of activism.In refuting the common and generalized narrative of failure that is used to describe the sixties (and can be extended to the seventies), Julie Stephens raises the many ways that the dominant ethos of the time was “revolutionised by the radicalism of the period, but in ways that bore little resemblance to the announced intentions of activists and participants themselves” (121). Further, she argues that the “extraordinary and paradoxical aspects of the anti-disciplinary protest of the period were that while it worked to collapse the division between opposition and complicity and problematised received understandings of the political, at the same time it reaffirmed its commitment to political involvement as an emancipatory, collective endeavour” (126).Many foresaw the political challenge of counterculture. From the belly of the beast, in 1975, Craig McGregor wrote that countercultures are “a crucial part of conventional society; and eventually they will be judged on how successful they transform it” (43). In arguing that permaculture is an assemblage and global network of practices, we contribute to a description of the shifting dynamic between dominant paradigms and counterculture that was identified by McGregor at the time and Stephens retrospectively, and we open up possibilities for reexamining an important moment in the history of Australian protest movements.Permaculture: Historical Context Together with practical manuals and theoretical texts permaculture has produced its foundation myths, centred around two father figures, Bill Mollison and David Holmgren. The pair, we read in accounts on the history of permaculture, met in the 1970s in Hobart at the University of Tasmania, where Mollison, after a polymath career, was a senior lecturer in Environmental Psychology, and Holmgren a student. Together they wrote the first article on permaculture in 1976 for the Organic Farmer and Gardener magazine (Grayson and Payne), which together with the dissemination of ideas via radio, captured the social imagination of the time. Two years later Holmgren and Mollison published the book Permaculture One: A Perennial Agricultural System for Human Settlements (Mollison and Holmgren).These texts and Mollison’s talks articulated ideas and desires and most importantly proposed solutions about living on the land, and led to the creation of the first ecovillage in Australia, Max Lindegger’s Crystal Waters in South East Queensland, the first permaculture magazine (titled Permaculture), and the beginning of the permaculture network (Grayson and Payne). In 1979 Mollison taught the first permaculture course, and published the second book. Grayson and Payne stress how permaculture media practices, such as the radio interview mentioned above and publications like Permaculture Magazine and Permaculture International Journal were key factors in the spreading of the design system and building a global network.The ideas developed around the concept of permaculture were shaped by, and in turned contributed to shape, the social climate of the late 1960s and early 1970s that captured the discontent with both capitalism and the Cold War, and that coalesced in “alternative lifestyles groups” (Metcalf). In 1973, for instance, the Aquarius Festival in Nimbin was not only a countercultural landmark, but also the site of emergence of alternative experiments in living that found their embodiment in experimental housing design (Stickells). The same interest in technological innovation mixed with rural skills animated one of permaculture’s precursors, the “back to the land movement” and its attempt “to blend rural traditionalism and technological and ideological modernity” (Grayson).This character of remix remains one of the characteristics of permaculture. Unlike movements based mostly on escape from the mainstream, permaculture offered a repertoire, and a system of adaptable solutions to live both in the country and the city. Like many aspects of the “alternative lifestyle” counterculture, permaculture was and is intensely biopolitical in the sense that it is concerned with the management of life itself “from below”: one’s own, people’s life and life on planet earth more generally. This understanding of biopolitics as power of life rather than over life is translated in permaculture into malleable design processes across a range of diversified practices. These are at the basis of the endurance of permaculture beyond the experiments in alternative lifestyles.In distinguishing it from sustainability (a contested concept among permaculture practitioners, some of whom prefer the notion of “planning for abundance”), Barry sees permaculture as:locally based and robustly contextualized implementations of sustainability, based on the notion that there is no ‘one size fits all’ model of sustainability. Permaculture, though rightly wary of more mainstream, reformist, and ‘business as usual’ accounts of sustainability can be viewed as a particular localized, and resilience-based conceptualization of sustainable living and the creation of ‘sustainable communities’. (83)The adaptability of permaculture to diverse solutions is stressed by Molly Scott-Cato, who, following David Holmgren, defines it as follows: “Permaculture is not a set of rules; it is a process of design based around principles found in the natural world, of cooperation and mutually beneficial relationships, and translating these principles into actions” (176).Permaculture Practice as Assemblage Scott Cato’s definition of permaculture helps us to understand both its conceptual framework as it is set out in permaculture manuals and textbooks, and the way it operates in practice at an individual, local, regional, national and global level, as an assemblage. Using the idea of assemblage, as defined by Jane Bennett, we are able to understand permaculture as part of an “ad hoc grouping”, a “collectivity” made up of many types of actors, humans, non humans, nature and culture, whose “coherence co-exists with energies and countercultures that exceed and confound it” (445-6). Put slightly differently, permaculture is part of “living” assemblage whose existence is not dependent on or governed by a “central power”. Nor can it be influenced by any single entity or member (445-6). Rather, permaculture is a “complex, gigantic whole” that is “made up variously, of somatic, technological, cultural, and atmospheric elements” (447).In considering permaculture as an assemblage that includes countercultural elements, we specifically adhere to John Law’s description of Actor Network Theory as an approach that relies on an empirical foundation rather than a theoretical one in order to “tell stories about ‘how’ relationships assemble or don’t” (141). The hybrid nature of permaculture design involving both human and non human stakeholders and their social and material dependencies can be understood as an “assembly” or “thing,” where everything not only plays its part relationally but where “matters of fact” are combined with “matters of concern” (Latour, "Critique"). As Barry explains, permaculture is a “holistic and systems-based approach to understanding and designing human-nature relations” (82). Permaculture principles are based on the enactment of interconnections, continuous feedback and reshuffling among plants, humans, animals, chemistry, social life, things, energy, built and natural environment, and tools.Bruno Latour calls this kind of relationality a “sphere” or a “network” that comprises of many interconnected nodes (Latour, "Actor-Network" 31). The connections between the nodes are not arbitrary, they are based on “associations” that dissolve the “micro-macro distinctions” of near and far, emphasizing the “global entity” of networks (361-381). Not everything is globalised but the global networks that structure the planet affect everything and everyone. In the context of permaculture, we argue that despite being highly connected through a network of digital and analogue platforms, the movement remains localised. In other words, permaculture is both local and global articulating global matters of concern such as food production, renewable energy sources, and ecological wellbeing in deeply localised variants.These address how the matters of concerns engendered by global networks in specific places interact with local elements. A community based permaculture practice in a desert area, for instance, will engage with storing renewable energy, or growing food crops and maintaining a stable ecology using the same twelve design principles and ethics as an educational business doing rooftop permaculture in a major urban centre. The localised applications, however, will result in a very different permaculture assemblage of animals, plants, technologies, people, affects, discourses, pedagogies, media, images, and resources.Similarly, if we consider permaculture as a network of interconnected nodes on a larger scale, such as in the case of national organisations, we can see how each node provides a counterpoint that models ecological best practices with respect to ingrained everyday ways of doing things, corporate and conventional agriculture, and so on. This adaptability and ability to effect practices has meant that permaculture’s sphere of influence has grown to include public institutions, such as city councils, public and private spaces, and schools.A short description of some of the nodes in the evolving permaculture assemblage in Sydney, where we live, is an example of the way permaculture has advanced from its alternative lifestyle beginnings to become part of the repertoire of contemporary activism. These practices, in turn, make room for accepted ways of doing things to move in new directions. In this assemblage each constellation operates within well established sites: local councils, public spaces, community groups, and businesses, while changing the conventional way these sites operate.The permaculture assemblage in Sydney includes individuals and communities in local groups coordinated in a city-wide network, Permaculture Sydney, connected to similar regional networks along the NSW seaboard; local government initiatives, such as in Randwick, Sydney, and Pittwater and policies like Sustainable City Living; community gardens like the inner city food forest at Angel Street or the hybrid public open park and educational space at the Permaculture Interpretive Garden; private permaculture gardens; experiments in grassroot urban permaculture and in urban agriculture; gardening, education and landscape business specialising in permaculture design, like Milkwood and Sydney Organic Gardens; loose groups of permaculturalists gathering around projects, such as Permablitz Sydney; media personalities and programs, as in the case of the hugely successful garden show Gardening Australia hosted by Costa Georgiadis; germane organisations dedicated to food sovereignty or seed saving, the Transition Towns movement; farmers’ markets and food coops; and multifarious private/public sustainability initiatives.Permaculture is a set of practices that, in themselves are not inherently “against” anything, yet empower people to form their own lifestyles and communities. After all, permaculture is a design system, a way to analyse space, and body of knowledge based on set principles and ethics. The identification of permaculture as a form of activism, or indeed as countercultural, is externally imposed, and therefore contingent on the ways conventional forms of housing and food production are understood as being in opposition.As we have shown elsewhere (2014) thinking through design practices as assemblages can describe hybrid forms of participation based on relationships to broader political movements, disciplines and organisations.Use Edges and Value the Marginal The eleventh permaculture design principle calls for an appreciation of the marginal and the edge: “The interface between things is where the most interesting events take place. These are often the most valuable, diverse and productive elements in the system” (permacultureprinciples.com). In other words the edge is understood as the site where things come together generating new possible paths and interactions. In this paper we have taken this metaphor to think through the relations between permaculture and counterculture. We argued that permaculture emerged from the countercultural ferment of the late 1960s and 1970s and intersected with other fringe alternative lifestyle experiments. In its contemporary form the “counter” value needs to be understood as counterpoint rather than as a position of pure oppositionality to the mainstream.The edge in permaculture is not a boundary on the periphery of a design, but a site of interconnection, hybridity and exchange, that produces adaptable and different possibilities. Similarly permaculture shares with forms of contemporary activism “flexible action repertoires” (Mayer 203) able to interconnect and traverse diverse contexts, including mainstream institutions. Permaculture deploys an action repertoire that integrates not segregates and that is aimed at inviting a shift in everyday practices and at doing things differently: differently from the mainstream and from the way global capital operates, without claiming to be in a position outside global capital flows. In brief, the assemblages of practices, ideas, and people generated by permaculture, like the ones described in this paper, as a counterpoint bring together discordant elements on equal terms.ReferencesBarry, John. The Politics of Actually Existing Unsustainability: Human Flourishing in a Climate-Changed, Carbon Constrained World. 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