Myxobacteria from animal dung pellets collected from northwestern Himalayas: A new source of di-isobutyl phthalate.

Myxobacteria have emerged as a rich manufacturer of a wide array of natural products captivating both the academic and drug discovery communities. Attempts to unearth novel bioactive, myxobacteria from unexploited habitats are far from exhaustion. This study reports the isolation of myxobacteria from dung pellets collected from various regions of northwestern Himalayas. The isolated myxobacteria were functionally characterized to evaluate their bioactive capability. Of all the isolates, ST/P/71 exhibited broad range activities such as anticancer against all the four human cancer cell lines with IC50 in range of 2.03-9.65 µg/ml, antimicrobial against all the tested human pathogens, also exhibiting biofilm inhibition with MBIC50 at 10.4 µg/ml against Salmonella typhimurium. Consequently, ST/P/71 was chosen for fermentation and isolation of bioactive secondary metabolite through semi-preparative HPLC. It yielded compound 1, characterized as di-isobutyl phthalate (DiBP) based on nuclear magnetic resonance (NMR) and mass data. DiBP exhibited promising cytotoxic activity against the lung cancer cell line (A549) at an IC50 values 3.09 µg/ml and biofilm inhibition activity against Bacillus subtilis and Salmonella typhimurium with MBIC50 2.703 and 9.263 µg/ml, respectively. ST/P/71 was identified as Myxococcus fulvus. Thus, M. fulvus ST/P/71 isolated from northwestern Himalayas is a new source of DiBP.

Analysis of UAV Thermal Soaring via Hawk-Inspired Swarm Interaction.

A swarm of unmanned aerial vehicles (UAVs) can be used for many applications, including disaster relief, search and rescue, and establishing communication networks, due to its mobility, scalability, and robustness to failure. However, a UAV swarm's performance is typically limited by each agent's stored energy. Recent works have considered the usage of thermals, or vertical updrafts of warm air, to address this issue. One challenge lies in a swarm of UAVs detecting and taking advantage of these thermals. Inspired by hawks, a swarm could take advantage of thermals better than individuals due to the swarm's distributed sensing abilities. To determine which emergent behaviors increase survival time, simulation software was created to test the behavioral models of UAV gliders around thermals. For simplicity and robustness, agents operate with limited information about other agents. The UAVs' motion was implemented as a Boids model, replicating the behavior of flocking birds through cohesion, separation, and alignment forces. Agents equipped with a modified behavioral model exhibit dynamic flocking behavior, including relative ascension-based cohesion and relative height-based separation and alignment. The simulation results show the agents flocking to thermals and improving swarm survival. These findings present a promising method to extend the flight time of autonomous UAV swarms.

Estimating the Burden of Illness of Relapsed Follicular Lymphoma and Marginal Zone Lymphoma in Ontario, Canada.

BACKGROUND: Many patients with advanced follicular lymphoma (FL) and marginal zone lymphoma (MZL) relapse after first-line chemotherapy. OBJECTIVE: To examine healthcare resource utilization (HCRU) and cost, treatment patterns, progression, and survival of patients with FL and MZL who relapse after first-line treatment, in Ontario, Canada. METHODS: A retrospective, administrative data study identified patients with relapsed FL and MZL (1 January 2005-31 December 2018). Patients were followed for up to three years post relapse to assess HCRU, healthcare costs, time to next treatment (TTNT), and overall survival (OS), stratified by first- and second-line treatment. RESULTS: The study identified 285 FL and 68 MZL cases who relapsed after first-line treatment. Average duration of first-line treatment was 12.4 and 13.4 months for FL and MZL patients, respectively. Drug (35.9%) and cancer clinic costs (28.1%) were major contributors to higher costs in year 1. Three-year OS was 83.9% after FL and 74.2% after MZL relapse. No statistically significant differences were observed in TTNT and OS between patients with FL who received R-CHOP/R-CVP/BR in the first line only versus both the first- and second- line. A total of 31% of FL and 34% of MZL patients progressed to third-line treatment within three years of initial relapse. CONCLUSION: Relapsing and remitting nature of FL and MZL in a subset of patients results in substantial burden to patients and the healthcare system.

Estimating the Associated Burden of Illness and Healthcare Utilization of Newly Diagnosed Patients Aged ≥65 with Mantle Cell Lymphoma (MCL) in Ontario, Canada.

BACKGROUND: With the emergence of therapies for mantle cell lymphoma (MCL), understanding the treatment patterns and burden of illness among older patients with MCL in Canada is essential to inform decision making. METHODS: A retrospective study using administrative data matched individuals aged ≥65 who were newly diagnosed with MCL between 1 January 2013 and 31 December 2016 with general population controls. Cases were followed for up to 3 years in order to assess healthcare resource utilization (HCRU), healthcare costs, time to next treatment or death (TTNTD), and overall survival (OS); all were stratified according to first-line treatment. RESULTS: This study matched 159 MCL patients to 636 controls. Direct healthcare costs were highest among MCL patients in the first year following diagnosis (Y1: CAD 77,555 ± 40,789), decreased subsequently (Y2: CAD 40,093 ± 28,720; Y3: CAD 36,059 ± 36,303), and were consistently higher than the costs for controls. The 3-year OS after MCL diagnosis was 68.6%, with patients receiving bendamustine + rituximab (BR) experiencing a significantly higher OS compared to patients treated with other regimens (72.4% vs. 55.6%, p = 0.041). Approximately 40.9% of MCL patients initiated a second-line therapy or died within 3 years. CONCLUSION: Newly diagnosed MCL presents a substantial burden to the healthcare system, with almost half of all patients progressing to a second-line therapy or death within 3 years.

Lorlatinib Effectiveness and Quality-of-Life in Patients with ALK-Positive NSCLC Who Had Failed Second-Generation ALK Inhibitors: Canadian Real-World Experience.

Lorlatinib is the only targeted therapy approved in Canada to treat patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) whose tumor has progressed despite treatment with second-generation ALK tyrosine kinase inhibitor (TKI), a patient population with high unmet need and lack of publicly reimbursed targeted treatments in Canada. We prospectively examined the real-world effectiveness and impact of lorlatinib on quality-of-life in 59 lorlatinib-treated patients, characterized as: median age of 62.0 years; 47.5% were female; 32.2% had central nervous system metastases; 50.8% had 2+ prior ALK TKI lines; and alectinib was the most common ALK TKI (72.9%) administered before lorlatinib, including 44.1% who received first-line alectinib. With a median follow-up of 15.3 months (IQR: 6.2-19.2), median time-to-treatment discontinuation of lorlatinib was 15.3 months (95% CI: 7.9-not reached), with 54.2% (95% CI: 40.8-65.9%) of patients without treatment discontinuation at 12 months. At baseline, the mean health utility score (HUS) was 0.744 (SD: 0.200). At 3 months, patients receiving lorlatinib demonstrated a 0.069 (95% CI: 0.020-0.118; p = 0.007) average HUS increase over baseline; HUS was maintained at 6 and 12 months. Thus, patients with ALK-positive NSCLC post second-generation ALK TKI remained on lorlatinib for a meaningful duration of time while their quality-of-life was preserved.

Influence of aerosol radiative effects on surface temperature and snow melt in the Himalayan region.

Recent increases in surface temperature and snow melt acceleration in the Himalayan region are influenced by many factors. Here we investigate the influence of absorbing aerosols, including black carbon and dust, on surface temperature and snow melt in western, central, and eastern parts of the India-Nepal Himalayan region (INHR). We compare 40-y simulations (1971-2010) one with all evolving forcing agents representative of a present-day aerosol scenario, compared to a low aerosol forcing scenario. The difference between these scenarios shows a significant increase in surface air temperature, with higher warming in parts of Western and Central Himalaya (~0.2-2 °C) in the months of April and May. Higher absorbing aerosol (BC and dust abundance) both at the surface and in the atmospheric column, in the present-day aerosol simulations, led to increases in atmospheric radiative forcing and surface shortwave heating rate forcing (SWHRF), compared to the low aerosol forcing case. Therefore, the absorbing aerosols cause anomalous atmospheric heat energy transfer to land due to high surface SWHRF and changes in surface energy flux, leading to snow melt. The present model version did not parameterize snow albedo feedback, which would increase the magnitudes of the changes simulated here.

Evaluation of the simulated aerosol optical properties over India: COALESCE model inter-comparison of three GCMs with ground and satellite observations.

Within the framework of COALESCE project (Carbonaceous aerosol emissions, source apportionment, and climate impacts) initiative, spatio-temporal distribution of aerosol optical properties from three general circulation models are evaluated against aerosol data from satellite observations (MODIS and CALIPSO) and ground-based measurements (AERONET) for the period 2005-2014. The GCMs, NICAM-SPRINTARS (N-S), ECHAM6.3-HAM2.3 (E-H), CAM5.3 (CAM), input with identical emissions from the SMoG-India-v1 emission inventory over India nested in the CEDS global inventory, including all emission sectors except sea salt and soil dust. The annual mean total aerosol optical depth (AOD) averaged over the Indian land region is 0.38, 0.27, and 0.17 from the N-S, CAM, and E-H models respectively, while the annual mean value from the MODIS observational dataset is 0.43. Single scattering albedo predicted by E-H is lower compared to CAM and N-S while model predictions of Angstrom exponent are closer to MERRA2 dataset. However, the average total aerosol column burden over Indian landmass simulated by the models is very close and comparable to the reanalysis results. Statistical analysis of AOD between model and AERONET measurements at nine sites shows that the root mean square error varies from 0.1 to 0.4 and the index of agreement (average value) is ∼0.4. The aerosol emission and transport models, methodology for calculation of aerosol optical properties and their mixing states contributes to the diversity in the results from various models. The present study provides an analysis of limitations and uncertainties contributing to the differences between the simulations and observations, and the inter-model diversity.

Global health burden of ambient PM2.5 and the contribution of anthropogenic black carbon and organic aerosols.

Chronic exposure to fine particulate matter (PM2.5) poses a major global health risk, commonly assessed by assuming equivalent toxicity for different PM2.5 constituents. We used a data-informed global atmospheric model and recent exposure-response functions to calculate the health burden of ambient PM2.5 from ten source categories. We estimate 4.23 (95% confidence interval 3.0-6.14) million excess deaths annually from the exposure to ambient PM2.5. We distinguished contributions and major sources of black carbon (BC), primary organic aerosols (POA) and anthropogenic secondary organic aerosols (aSOA). These components make up to ∼20% of the total PM2.5 in South and East Asia and East Africa. We find that domestic energy use by the burning of solid biofuels is the largest contributor to ambient BC, POA and aSOA globally. Epidemiological and toxicological studies indicate that these compounds may be relatively more hazardous than other PM2.5 compounds such as soluble salts, related to their high potential to inflict oxidative stress. We performed sensitivity analyses by considering these species to be more harmful compared to other compounds in PM2.5, as suggested by their oxidative potential using a range of potential relative risks. These analyses show that domestic energy use emerges as the leading cause of excess mortality attributable to ambient PM2.5, notably in Asia and Africa. We acknowledge the uncertainties inherent in our assumed enhanced toxicity of the anthropogenic organic and BC aerosol components, which suggest the need to better understand the mechanisms and magnitude of the associated health risks and the consequences for regulatory policies. However our assessment of the importance of emissions from domestic energy use as a cause of premature mortality is robust to a range of assumptions about the magnitude of the excess risk.

How healthy are children one year after discharge from nutritional rehabilitation centres?

Nutritional rehabilitation centres (NRCs) have been established to ensure the nutritional recovery of severely malnourished children. The long-term nutritional outcomes in children discharged from NRCs have not been described. In this retrospective cohort study, the nutritional status of 514 children was assessed one year after discharge. Household and maternal data, as well as data regarding variables related to the children's stay at the NRC, were collected. A total of 33.4% had moderate malnutrition and 11.7% had severe malnutrition. The mean weight for height Z-score at admission, discharge and one year after discharge were -3.61, -1.90 and -2.34, respectively. Thus, long-term monitoring and follow-up of children discharged from NRCs till they achieve normal nutritional status is mandatory.

Time spent being malnourished during the first five years of life! An unseen aspect of child malnutrition.

The burden of malnutrition is often estimated in terms of 'prevalence' without considering two important contributing factors: incidence and duration. To illustrate this, we conducted a community-based retrospective cohort study involving 24,278 children enrolled in an integrated child development scheme in India. Anthropometric data of study participants from birth to five years of age were collected from the growth charts maintained by Anganwadi workers. Of all the growth charts reviewed, 1460 (6.0%) children died before their fifth birthday and 4013 (16.5%) were excluded after initial screening because either the growth chart was incomplete (4.8%) or had missing entries (11.7%). Of the remaining 20,265 children included in the study, in the first five years of their life, 35.6% suffered from exclusive moderate malnourishment and 9.4% from severe malnourishment. The most common age groups for the onset of moderate and severe malnutrition were 9-11 months and 12-15 months, respectively. The mode, median and mean duration of time spent by children being severely underweight was 3, 7 and 8.4 months respectively, and being moderately underweight was 8, 11 and 15.1 months, respectively. Thus, a comprehensive strategy for preventing the onset of malnutrition (both moderate and severe) among children is urgently needed.

Short hybrid peptides incorporating ß- and γ-amino acids as antimicrobial agents.

The peptides containing ß- and γ-amino acids, LA-Lys-PEA, P1; LA-Lys-ß3,3-Ac6c-PEA, P2; LA-Orn-ß3,3-Ac6c-PEA, P3; LA-Lys-Gpn-PEA, P4; LA-Orn-Gpn-PEA, P5; LA-Lys-γ4-Phe-PEA, P6, LA-γ4-Leu-Lys-PEA, P7 and LA-ß3,3-Pip(Ac)-Lys-PEA, P8 were synthesized, characterized and evaluated against Gram-positive and Gram-negative bacteria. Among all, peptides P2, P3, P4 and P5 exhibited potent activity (MIC 6.25µM) against S. aureus MTCC 737 and P. aeruginosa MTCC 424. In order to understand the efficacy of peptides and mechanism of action, time kill kinetics and fluorescence microscopic studies were performed against S. aureus and P. aeruginosa for the peptides P2, P3, P4 and P5. P4 took half time to show the bactericidal effect on P. aeruginosa and S. aureus in comparison to P2 at their 2x MICs. Fluorescence microscopic studies suggested that peptides P2 and P4 both killed the bacteria via membrane disruption. Further, P4 exhibited lowest haemolytic activity among active peptides and negligible cytotoxic activity against human cancer cell lines A-549, PC-3 and HCT-116 at its MIC.