Aminobenzofuran-containing analogues of proximicins exhibit higher antiproliferative activity against human UG-87 glioblastoma cells compared to temozolomide

A new series of proximicin analogues containing a benzofuran moiety as the replacement of the di-furan scaffold of the parent compound were synthesised and evaluated for their anti-proliferative activities against human glioblastoma cells U-87 MG. Proximicins A, B, and C are secondary metabolites produced by Verrucosispora Fiedleri MG-37, a Gram-positive actinomycete isolated from deep-sea sediment. Proximicins exhibit significant cytotoxic and apoptotic effects in a number of tumour cell lines, although further investigations on these natural products biological activity are hampered by the challenging synthesis of their constitutive di-furan unit. Therefore, the easily-synthesisable benzofuran ring was elected as a replacement of the di-furan platform, and a library of proximicin analogues was prepared in which different substituents were introduced at both the N-terminus and C-terminus of the benzofuran core unit. The novel compounds were tested against U-87 MG, as it was previously found that proximicins targeted this cancerous cell line, and the human healthy cell line WI-38. Temozolomide, the chemotherapeutic agent of choice for the treatment of glioblastoma, was used as a control. Analysis of growth inhibitory concentration values revealed that a number of furan-benzofuran-containing proximicin analogues, including 23(16) (IC50 U-87 MG = 6.54 μg mL-1) exhibited higher antiproliferative activity against glioblastoma cells compared to both proximicins A-C and temozolomide (IC50 U-87 MG = 29.19 μg mL-1) in U-87 MG

Aminobenzofuran-containing analogues of proximicins exhibit higher antiproliferative activity against human UG-87 glioblastoma cells compared to temozolomide

open access articleA new series of proximicin analogues containing a benzofuran moiety as the replacement of the di-furan scaffold of the parent compound were synthesised and evaluated for their anti-proliferative activities against human glioblastoma cells U-87 MG. Proximicins A, B, and C are secondary metabolites produced by Verrucosispora Fiedleri MG-37, a Gram-positive actinomycete isolated from deep-sea sediment. Proximicins exhibit significant cytotoxic and apoptotic effects in a number of tumour cell lines, although further investigations on these natural products biological activity are hampered by the challenging synthesis of their constitutive di-furan unit. Therefore, the easily-synthesisable benzofuran ring was elected as a replacement of the di-furan platform, and a library of proximicin analogues was prepared in which different substituents were introduced at both the N-terminus and C-terminus of the benzofuran core unit. The novel compounds were tested against U-87 MG, as it was previously found that proximicins targeted this cancerous cell line, and the human healthy cell line WI-38. Temozolomide, the chemotherapeutic agent of choice for the treatment of glioblastoma, was used as a control. Analysis of growth inhibitory concentration values revealed that a number of furan-benzofuran-containing proximicin analogues, including 23(16) (IC50 U-87 MG = 6.54 μg mL−1) exhibited higher antiproliferative activity against glioblastoma cells compared to both proximicins A–C and temozolomide (IC50 U-87 MG = 29.19 μg mL−1) in U-87 MG

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Background: Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. // Methods: We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung's disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. // Findings: We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung's disease) from 264 hospitals (89 in high-income countries, 166 in middle-income countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in low-income countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. // Interpretation: Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between low-income, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

PENGARUH LINGKUNGAN KERJA DAN KNOWLEDGE SHARING TERHADAP KINERJA PEGAWAI (STUDI PADA PUSKESMAS SUNGAI DURI KECAMATAN SUNGAI RAYA KABUPATEN BENGKAYANG)

Kinerja SDM menjadi aspek yang sangat penting dalam pencapaian tujuan organisasi kedepannya. Kinerja organisasi salah satunya ditentukan oleh kinerja SDM. Untuk mencapai kinerja kinerja SDM yang tinggi, perilaku knowledge sharing diantara anggota organisasi sangat diharapkan. Lingkungan kerja yang terdiri dari   lingkungan kerja fisik dan non fisik turut menentukan kinerja SDM.Penelitian ini bertujuan untuk mengetahui apakah ada pengaruh lingkungan kerja dan knowledge sharing terhadap kinerja pegawai Puskesmas Sungai Duri. Jumlah sampel dalam penelitian ini sebanyak 48 responden. Teknik penarikan sampel yang digunakan adalah teknik sampling jenuh. Penelitian ini menggunakan teknik analis data regresi linear berganda dengan menggunakan SPSS versi 21.0. Hasil penelitian menunjukkan bahwa lingkungan kerja  dan knowledge sharing berpengaruh positif dan signifikan terhadap kinerja pegawai Puskesmas Sungai Duri dengan koefisien determinasi (R2) sebesar 72,3%, sedangkan sisanya sebesar 27,7% dipengaruhi oleh variabel lain yang tidak diteliti dalam penelitian ini. Kata kunci: Lingkungan Kerja, Knowledge Sharing, dan Kinerja Pegawai.  

Scleroderma Renal Crisis in a Case of Mixed Connective Tissue Disease Treated Successfully with Angiotensin-Converting Enzyme Inhibitors

Mixed connective tissue disease (MCTD) is a rheumatic disease syndrome with overlapping features of scleroderma, systemic lupus erythematosus, and polymyositis. An extremely rare but serious complication that can occur in MCTD is scleroderma renal crisis (SRC). There have been different approaches to the treatment of SRC associated with MCTD. We present a case of MCTD with chronic features of Raynaud’s phenomenon, dermatomyositis, and thrombocytopenia complicated with acute SRC which showed a great response to ACE inhibitors. Here, we advise the early and aggressive use of ACE inhibitors as soon as SRC is suspected

Laser Registration and Supervisory Control of neuroArm Robotic Surgical System

This paper illustrates the concept of an algorithm to register specified markers on the neuroArm surgical manipulators, an image-guided MR-compatible tele-operated robot for microsurgery and stereotaxy. Two range-finding algorithms, namely time-of-flight and phase-shift, are evaluated for registration and supervisory control. The time-of-flight approach is implemented in a semi-field experiment to determine the precise position of a tiny retro-reflective moving object. The moving object simulates a surgical tool tip. The tool is a target that would be connected to the neuroArm end-effector during surgery inside the magnet bore of the MR imaging system. In order to apply flight approach, a 905-nm pulsed laser diode and an avalanche photodiode are utilized as the transmitter and receiver, respectively. For the experiment, a high frequency time to digital converter was designed using a field-programmable gate arrays. In the phase-shift approach, a continuous green laser beam with a wavelength of 530 nm was used as the transmitter. Results showed that a positioning error of 0.1 mm occurred when the scanner-target point distance was set in the range of 2.5 to 3 meters. The effectiveness of this non-contact approach exhibited that the method could be employed as an alternative for conventional mechanical registration arm. Furthermore, the approach is not limited by physical contact and extension of joint angles

Synthesis, Isolation, Identification and Characterization of a Drug-Excipient Interaction Degradation Impurity in Pramipexole by HPLC, LC/MS and NMR

A drug-excipient interaction impurity associated with the degradation process of pramipexole was isolated. The impurity was detected during the stability study of pramipexole extended-release tablets. It was found at a relative retention time of 0.88 with respect to pramipexole, using the pramipexole gradient HPLC-UV detection method described in the USP. The structure of the impurity was identified and fully characterized using high resolution mass spectrometry, IR and NMR techniques, as presented herein. The degradation impurity was identified as (S)-N2-(methoxymethyl)-N6-propyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine. The drug-excipient interaction mechanism of its formation was proposed. An efficient and straightforward synthetic approach was developed to prepare the degradation impurity to confirm its proposed degradation pathway and structure

A prospective diagnostic study on povidone–iodine retention in lesions suspected to be squamous cell carcinoma or keratoacanthoma

While dermatoscopy improves diagnostic accuracy for raised nonpigmented lesions, those with white surface keratin can be problematical. We investigated whether retention of povidone-iodine by surface keratin provides a clue to benignity.We performed a retrospective pilot study (n\ua0=\ua057) followed by a prospective study (n\ua0=\ua0117) on raised nonpigmented lesions with white surface keratin. An initial dermatoscopic image was taken of each lesion, povidone-iodine was applied and another image taken. Following lavage with 70% ethanol, a third image was acquired. The percentage surface area of residual povidone-iodine staining after lavage was recorded, and the results analysed.The optimal cut-off point of residual staining was 80%, where values of ≤80% pointed to malignancy. At this cut-off, the OR for lesions with values ≤80% to be truly malignant in the retrospective set was 4.03 (95% CI: 2.1-7.6) and the AUC was 0.7 (95% CI: 0.62-0.78). For the prospective set, the corresponding OR was 2.3 (95% CI: 1.4-3.7) and the AUC was 0.62 (95% CI: 0.55-0.68).This study presents evidence that povidone-iodine retention may have a degree of efficacy in distinguishing benign from malignant keratotic lesions. Further study is warranted