Green nanotechnology of MGF‑AuNPs for immunomodulatory intervention in prostate cancer therapy

Abstract Men with castration-resistant prostate cancer (CRPC) face poor prognosis and increased risk of treatment-incurred adverse effects resulting in one of the highest mortalities among patient population globally. Immune cells act as double-edged sword depending on the tumor microenvironment, which leads to increased infiltration of pro-tumor (M2) macrophages. Development of new immunomodulatory therapeutic agents capable of targeting the tumor microenvironment, and hence orchestrating the transformation of pro-tumor M2 macrophages to anti-tumor M1, would substantially improve treatment outcomes of CRPC patients. We report, herein, Mangiferin functionalized gold nanoparticulate agent (MGF-AuNPs) and its immunomodulatory characteristics in treating prostate cancer. We provide evidence of immunomodulatory intervention of MGF-AuNPs in prostate cancers through observations of enhanced levels of anti-tumor cytokines (IL-12 and TNF-α) with concomitant reductions in the levels of pro-tumor cytokines (IL-10 and IL-6). In the MGF-AuNPs treated groups, IL-12 was elevated to ten-fold while TNF-α was elevated to about 50-fold, while IL-10 and IL-6 were reduced by two-fold. Ability of MGF-AuNPs to target splenic macrophages is invoked via targeting of NF-kB signaling pathway. Finally, therapeutic efficacy of MGF-AuNPs, in treating prostate cancer in vivo in tumor bearing mice, is described taking into consideration various immunomodulatory interventions triggered by this green nanotechnology-based nanomedicine agent

Burnout among surgeons before and during the SARS-CoV-2 pandemic: an international survey

Background: SARS-CoV-2 pandemic has had many significant impacts within the surgical realm, and surgeons have been obligated to reconsider almost every aspect of daily clinical practice. Methods: This is a cross-sectional study reported in compliance with the CHERRIES guidelines and conducted through an online platform from June 14th to July 15th, 2020. The primary outcome was the burden of burnout during the pandemic indicated by the validated Shirom-Melamed Burnout Measure. Results: Nine hundred fifty-four surgeons completed the survey. The median length of practice was 10 years; 78.2% included were male with a median age of 37 years old, 39.5% were consultants, 68.9% were general surgeons, and 55.7% were affiliated with an academic institution. Overall, there was a significant increase in the mean burnout score during the pandemic; longer years of practice and older age were significantly associated with less burnout. There were significant reductions in the median number of outpatient visits, operated cases, on-call hours, emergency visits, and research work, so, 48.2% of respondents felt that the training resources were insufficient. The majority (81.3%) of respondents reported that their hospitals were included in the management of COVID-19, 66.5% felt their roles had been minimized; 41% were asked to assist in non-surgical medical practices, and 37.6% of respondents were included in COVID-19 management. Conclusions: There was a significant burnout among trainees. Almost all aspects of clinical and research activities were affected with a significant reduction in the volume of research, outpatient clinic visits, surgical procedures, on-call hours, and emergency cases hindering the training. Trial registration: The study was registered on clicaltrials.gov "NCT04433286" on 16/06/2020

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

The Tale of a Choreographer, Her student, River and an endangered Heritage: Indu Mitha’s Qaseeda-i-Ilm of Jamal/ “An Ode to Wisdom and Beauty”

Choreographing in Pakistan since the 50’s, the country’s senior most 90+ years young classical dance maestro Indu Mitha has made trailblazing contributions within the Kalakshtera Bharata Natyam using North Indian music, interesting and contemporary content, while also producing more tableau forms of dance. In one of her recent solo pieces in the later style, titled “Qaseeda-i-Ilm of Jamal” or “An Ode to Wisdom and Beauty” Indu engages with symbolisms of a Hindu goddess of knowledge and Aesthetics_Saraswati and pays tribute to a forgotten dried up river of the same name. Indu Mitha allows the author, for whom and on whose body the dance is made, to bring in the forgotten river in her engagement with people’s histories of the land of present-day Pakistan and eventually facilitates her accessing of and embodying a pluralistic space of inter faith harmony which was occluded

Choreographing [in] Pakistan: Indu Mitha, Dancing Occluded histories in "The Land of the Pure"

This critical biography of Indu Mitha, a Pakistani dancer and choreographer, lays out an alternate, creative history of sixty-four years of post-Partition Pakistan. Her life and work enable choreographing an occluded space on stage and beyond, which I call space of hope --a space of alterity, a place where narratives countering the nation state boundaries enforced by the 1947 Partition of British India into the three independent states of Pakistan, India, and Bangladesh (1971). This space is not a post-colonial one, but is based on a longer shared historical specificity of South Asia. Indu Mitha's life and work enable this journey into occluded spaces, into an alternate history of sixty-four years of post-Partition Pakistan. These spaces of hope are foci to probing broader questions about the place of the outliers, i.e. Muslims in India, and non-Muslims and "non-Pakistanis" in Pakistan (Post 1971), in the aftermath of the 1947 Partition of India. This dissertation stages the untold history of these minority voices of classical dancers and musicians in Pakistan, and in the process questions whether their marginal statuses are due to factors connected to the aftermath of Partition, or to a redundant pre-colonial baggage, or both.By taking a creative approach to writing a shared history of Pakistan, India and Bangladesh beyond Partition, this dissertation presents controversial, contested histories that are closer to the ground realities of people in the region. Methodology involved triangulating Indu's bharata natyam, kathak and Uday Shankar choreographies with her life history, parallel to key moments of South Asian history from the early twentieth century to the first decade of the twenty-first century. This new "creative approach" brings together, for the first time, cutting edge work in the fields of post-colonial histories and Partition aftermath studies with dance history scholarship, in particular critical bharata natyam studies. This project uses the rich lyric mode and story-telling tradition of bharata natyam, syncrethic aspects of kathak, and the creative style of Indu's Uday Shankar repertoire to narrate alternative histories that have been silenced and/or ignored in official narratives. These histories call for a rethinking of the occluded inclusive and secular vision of founding father Jinnah as protector-general of the minorities

ANALISA DAN PERANCANGAN SISTEM INFORMASI JASA SIMPAN PINJAM PADA KOPERASI SEJAHTERA ABADI

ANALISA DAN PERANCANGAN SISTEM INFORMASI JASA SIMPAN PINJAM PADA KOPERASI SEJAHTERA ABADI

Characterization and Evaluation of Antimicrobial Potential of <i>Trigonella incise</i> (Linn) Mediated Biosynthesized Silver Nanoparticles

The goal of the research was to explore a new green method used to synthesize silver nanoparticles (Ag NPs) from an aqueous extract of Trigonella incise, which serves as a reducing and stabilizing agent. The obtained results showed an 85% yield of nanoparticles by using 2:5 (v/v) of 5% plant extract with a 0.5 M solution of AgNO3. Different techniques were used to characterize the synthesized Ag NPs, including X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), and UV–visible spectroscopy. The UV–visible spectra of green synthesized silver nanoparticles showed maximum absorption at a wavelength of 440 nm. The FT-IR studies revealed the stretching oscillation frequency of synthesized silver nanoparticles in the absorption band near 860 cm−1. Similarly, the bending and stretching oscillation frequencies of the NH function group were assigned to the band in the 3226 cm−1 and 1647 cm−1 regions. The bending vibration of C-O at 1159 cm−1 confirmed the carbonyl functional group that was also assigned to the small intensity band in the range of 2361 cm−1. The X-ray diffraction analysis of Ag NPs revealed four distinct diffraction peaks at 2θ of 38°, 45°, 65° and 78°, corresponds to (111), (200), (220) and (311) of the face-centered cubic shape. The round shape morphology of Ag NPs with a mean diameter in the range 20–80 nm was analyzed via SEM images. Furthermore, the nanoparticles showed more significant antimicrobial activity against Salmonella typhi (S. typhi) and Staphylococcus aureus (S. aureus) with an inhibition zone of 21.5 mm and 20.5 mm at 6 μg/mL concentrations, respectively, once compared to the standard reference. At concentrations of 2 µg/mL and 4 µg/mL, all of the bacterial strains showed moderate activity, with inhibition zones ranging from 11 mm to 18.5 mm. Even at high concentrations of AgNPs, S. typhi showed maximum resistance. The best antifungal activity was observed by synthesized Ag NPs against Candida albicans (C. albicans) with 21 mm zone of inhibition, as compared to a standard drug which gives 22 mm of inhibition. Therefore, we conclude that the antibacterial and antifungal activities showed satisfactory results from the synthesized Ag NPs

Heavy Metal (Arsenic) Induced Antibiotic Resistance among Extended-Spectrum &beta;-Lactamase (ESBL) Producing Bacteria of Nosocomial Origin

Antimicrobial resistance (AMR) is a leading cause of treatment failure for many infectious diseases worldwide. Improper overdosing and the misuse of antibiotics contributes significantly to the emergence of drug-resistant bacteria. The co-contamination of heavy metals and antibiotic compounds existing in the environment might also be involved in the spread of AMR. The current study was designed to test the efficacy of heavy metals (arsenic) induced AMR patterns in clinically isolated extended-spectrum &beta;-lactamase (ESBL) producing bacteria. A total of 300 clinically isolated ESBL-producing bacteria were collected from a tertiary care hospital in Lahore, Pakistan, with the demographic characteristics of patients. After the collection of bacterial isolates, these were reinoculated on agar media for reidentification purposes. Direct antimicrobial sensitivity testing (AST) for bacterial isolates by disk diffusion methods was used to determine the AST patterns with and without heavy metal. The heavy metal was concentrated in dilutions of 1.25 g/mL. The collected bacterial isolates were isolated from wounds (n = 63, 21%), urine (n = 112, 37.3%), blood (n = 43, 14.3%), pus (n = 49, 16.3%), and aspirate (n = 33, 11%) samples. From the total 300 bacterial isolates, n = 172 were Escherichia coli (57.3%), 57 were Klebsiella spp. (19%), 32 were Pseudomonas aeruginosa (10.6%), 21 were Proteus mirabilis (7%) and 18 were Enterobacter spp. (6%). Most of the antibiotic drugs were found resistant to tested bacteria. Colistin and Polymyxin-B showed the highest sensitivity against all tested bacteria, but when tested with heavy metals, these antibiotics were also found to be significantly resistant. We found that heavy metals induced the resistance capability in bacterial isolates, which leads to higher AMR patterns as compared to without heavy metal tested isolates. The results of the current study explored the heavy metal as an inducer of AMR and may contribute to the formation and spread of AMR in settings that are contaminated with heavy metals