Computational Modelling of the Interaction of Gold Nanoparticle with Lung Surfactant Monolayer

Copyright © Materials Research Society 2019. Lung surfactant (LS), a thin layer of phospholipids and proteins inside the alveolus of the lung is the first biological barrier to inhaled nanoparticles (NPs). LS stabilizes and protects the alveolus during its continuous compression and expansion by fine-Tuning the surface tension at the air-water interface. Previous modelling studies have reported the biophysical function of LS monolayer and its role, but many open questions regarding the consequences and interactions of airborne nano-sized particles with LS monolayer remain. In spite of gold nanoparticles (AuNPs) having a paramount role in biomedical applications, the understanding of the interactions between bare AuNPs (as pollutants) and LS monolayer components still unresolved. Continuous inhalation of NPs increases the possibility of lung ageing, reducing the normal lung functioning and promoting lung malfunction, and may induce serious lung diseases such as asthma, lung cancer, acute respiratory distress syndrome, and more. Different medical studies have shown that AuNPs can disrupt the routine lung functions of gold miners and promote respiratory diseases. In this work, coarse-grained molecular dynamics simulations are performed to gain an understanding of the interactions between bare AuNPs and LS monolayer components at the nanoscale. Different surface tensions of the monolayer are used to mimic the biological process of breathing (inhalation and exhalation). It is found that the NP affects the structure and packing of the lipids by disordering lipid tails. Overall, the analysed results suggest that bare AuNPs impede the normal biophysical function of the lung, a finding that has beneficial consequences to the potential development of treatments of various respiratory diseases

Survival and health economic outcomes in heart failure diagnosed at hospital admission versus community settings: a propensity-matched analysis

BACKGROUND AND AIMS: Most patients with heart failure (HF) are diagnosed following a hospital admission. The clinical and health economic impacts of index HF diagnosis made on admission to hospital versus community settings are not known. METHODS: We used the North West London Discover database to examine 34 208 patients receiving an index diagnosis of HF between January 2015 and December 2020. A propensity score-matched (PSM) cohort was identified to adjust for differences in socioeconomic status, cardiovascular risk and pre-diagnosis health resource utilisation cost. Outcomes were stratified by two pathways to index HF diagnosis: a 'hospital pathway' was defined by diagnosis following hospital admission; and a 'community pathway' by diagnosis via a general practitioner or outpatient services. The primary clinical and health economic endpoints were all-cause mortality and cost-consequence differential, respectively. RESULTS: The diagnosis of HF was via hospital pathway in 68% (23 273) of patients. The PSM cohort included 17 174 patients (8582 per group) and was matched across all selected confounders (p>0.05). The ratio of deaths per person-months at 24 months comparing community versus hospital diagnosis was 0.780 (95% CI 0.722 to 0.841, p<0.0001). By 72 months, the ratio of deaths was 0.960 (0.905 to 1.020, p=0.18). Diagnosis via hospital pathway incurred an overall extra longitudinal cost of £2485 per patient. CONCLUSIONS: Index diagnosis of HF through hospital admission continues to dominate and is associated with a significantly greater short-term risk of mortality and substantially increased long-term costs than if first diagnosed in the community. This study highlights the potential for community diagnosis-early, before symptoms necessitate hospitalisation-to improve both clinical and health economic outcomes

Hookworm Infection and Environmental Factors in Mbeya Region, Tanzania: A Cross-sectional, Population-based study.

Hookworm disease is one of the most common infections and cause of a high disease burden in the tropics and subtropics. Remotely sensed ecological data and model-based geostatistics have been used recently to identify areas in need for hookworm control. Cross-sectional interview data and stool samples from 6,375 participants from nine different sites in Mbeya region, south-western Tanzania, were collected as part of a cohort study. Hookworm infection was assessed by microscopy of duplicate Kato-Katz thick smears from one stool sample from each participant. A geographic information system was used to obtain remotely sensed environmental data such as land surface temperature (LST), vegetation cover, rainfall, and elevation, and combine them with hookworm infection data and with socio-demographic and behavioral data. Uni- and multivariable logistic regression was performed on sites separately and on the pooled dataset. Univariable analyses yielded significant associations for all ecological variables. Five ecological variables stayed significant in the final multivariable model: population density (odds ratio (OR) = 0.68; 95% confidence interval (CI) = 0.63-0.73), mean annual vegetation density (OR = 0.11; 95% CI = 0.06-0.18), mean annual LST during the day (OR = 0.81; 95% CI = 0.75-0.88), mean annual LST during the night (OR = 1.54; 95% CI = 1.44-1.64), and latrine coverage in household surroundings (OR = 1.02; 95% CI = 1.01-1.04). Interaction terms revealed substantial differences in associations of hookworm infection with population density, mean annual enhanced vegetation index, and latrine coverage between the two sites with the highest prevalence of infection. This study supports previous findings that remotely sensed data such as vegetation indices, LST, and elevation are strongly associated with hookworm prevalence. However, the results indicate that the influence of environmental conditions can differ substantially within a relatively small geographic area. The use of large-scale associations as a predictive tool on smaller scales is therefore problematic and should be handled with care

Outcomes of Multi-Drug Resistant Tuberculosis (MDR-TB) among a Cohort of South African Patients with High HIV Prevalence

Multidrug-resistant tuberculosis (MDR-TB) is a major clinical challenge, particularly in patients with human immunodeficiency virus (HIV) co-infection. MDR-TB treatment is increasingly available, but outcomes have not been well characterized. South Africa has provided MDR-TB treatment for a decade, and we evaluated outcomes by HIV status for patients enrolled between 2000 and 2004 prior to anti-retroviral access.We assessed treatment outcomes in a prospective cohort of patients with MDR-TB from eight provincial programs providing second line drugs. World Health Organization definitions were used. Results were stratified by HIV status.Seven hundred fifty seven patients with known HIV status were included in the final analysis, and HIV infection was documented in 287 (38%). Overall, 348 patients (46.0%) were successfully treated, 74 (9.8%) failed therapy, 177 (23.4%) died and 158 (20.9%) defaulted. Patients with HIV were slightly younger and less likely to be male compared to HIV negative patients. Patients with HIV were less likely to have a successful treatment outcome (40.0 vs. 49.6; P<0.05) and more likely to die (35.2 vs. 16.2; P<0.0001). In a competing risk survival analysis, patients with HIV had a higher hazard of death (HR: 2.33, P<0.0001). Low baseline weight (less than 45 kg and less than 60 kg) was also associated with a higher hazard of death (HR: 2.52, P<0.0001; and HR: 1.50, P<0.0001, respectively, compared to weight greater than 60 kg). Weight less than 45 kg had higher risk of failure (HR: 3.58, P<0.01). Any change in treatment regimen was associated with a higher hazard of default (HR: 2.86; 95% CI 1.55-5.29, P<0.001) and a lower hazard of death (HR: 0.63, P<0.05).In this MDR-TB treatment program patients with HIV infection and low weight had higher hazards of death. Overall treatment outcomes were poor. Efforts to improve treatment for MDR-TB are urgently needed

Characteristics and Treatment Outcomes of Patients with MDR and XDR Tuberculosis in a TB Referral Hospital in Beijing: A 13-Year Experience

Background: Information on treatment outcomes among hospitalized patients with multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) are scarce in China. Methodology/Principal Findings: We conducted this retrospective study to analyze the characteristics and treatment outcomes in MDR- and XDR-TB patients in the 309 Hospital in Beijing, China during 1996-2009. Socio-demographic and clinical data were retrieved from medical records and analyzed. Logistic regression analysis was performed to identify risk factors associated with poor treatment outcomes and Cox proportional hazards regression model was further used to determine risk factors associated with death in TB patients. Among the 3,551 non-repetitive hospitalized TB patients who had drug susceptibility testing (DST) results, 716 (20.2%) had MDR-TB and 51 (1.4%) had XDR-TB. A total of 3,270 patients who had medical records available were used for further analyses. Treatment success rates (cured and treatment completed) were 90.9%, 53.4% and 29.2% for patients with non-MDR-TB, patients with MDR-TB excluding XDR-TB and patients with XDR-TB, respectively. Independent risk factors associated with poor treatment outcomes in MDR-TB patients included being a migrant (adjusted OR = 1.77), smear-positivity at treatment onset (adjusted OR = 1.94) and not receiving 3 or more potentially effective drugs (adjusted OR = 3.87). Independent risk factors associated with poor treatment outcomes in XDR-TB patients were smear-positivity at treatment onset (adjusted OR = 10.42) and not receiving 3 or more potentially effective drugs (adjusted OR = 14.90). The independent risk factors associated with death in TB patients were having chronic obstructive pulmonary disease (adjusted HR = 5.25) and having hypertension (adjusted HR = 4.31). Conclusions/Significance: While overall satisfactory treatment success for non-MDR-TB patients was achieved, more intensive efforts should be made to better manage MDR- and XDR-TB cases in order to improve their treatment outcomes and to minimize further emergence of so-called totally drug-resistant TB cases. © 2011 Liu et al.published_or_final_versio

Genotype-Phenotype Characterization of Serial Mycobacterium tuberculosis Isolates in Bedaquiline-Resistant Tuberculosis.

BACKGROUND: Emerging resistance to bedaquiline (BDQ) threatens to undermine advances in the treatment of drug-resistant tuberculosis (DRTB). Characterizing serial Mycobacterium tuberculosis (Mtb) isolates collected during BDQ-based treatment can provide insights into the etiologies of BDQ resistance in this important group of DRTB patients. METHODS: We measured mycobacteria growth indicator tube (MGIT)-based BDQ minimum inhibitory concentrations (MICs) of Mtb isolates collected from 195 individuals with no prior BDQ exposure who were receiving BDQ-based treatment for DRTB. We conducted whole-genome sequencing on serial Mtb isolates from all participants who had any isolate with a BDQ MIC >1 collected before or after starting treatment (95 total Mtb isolates from 24 participants). RESULTS: Sixteen of 24 participants had BDQ-resistant TB (MGIT MIC ≥4 µg/mL) and 8 had BDQ-intermediate infections (MGIT MIC = 2 µg/mL). Participants with pre-existing resistance outnumbered those with resistance acquired during treatment, and 8 of 24 participants had polyclonal infections. BDQ resistance was observed across multiple Mtb strain types and involved a diverse catalog of mmpR5 (Rv0678) mutations, but no mutations in atpE or pepQ. Nine pairs of participants shared genetically similar isolates separated by <5 single nucleotide polymorphisms, concerning for potential transmitted BDQ resistance. CONCLUSIONS: BDQ-resistant TB can arise via multiple, overlapping processes, including transmission of strains with pre-existing resistance. Capturing the within-host diversity of these infections could potentially improve clinical diagnosis, population-level surveillance, and molecular diagnostic test development

Survival of Civilian and Prisoner Drug-Sensitive, Multi- and Extensive Drug- Resistant Tuberculosis Cohorts Prospectively Followed in Russia

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The importance of providing counselling and financial support to patients receiving treatment for multi-drug resistant TB: Mixed method qualitative and pilot intervention studies

Background: People with multi-drug resistant tuberculosis (MDR-TB) in low-income countries face many problems during treatment, and cure rates are low. The purpose of the study was (a) to identify and document the problems experienced by people receiving care for MDR-TB, and how they cope when support is not provided, to inform development of strategies; (b) to estimate the effectiveness of two resultant strategies, counselling alone, and joint counselling and financial support, of increasing DOTS-plus treatment success under routine programme conditions. Methods. A mixed-method study comprising a formative qualitative study, pilot intervention study and explanatory qualitative study to better understand barriers to completion of treatment for MDR-TB. Participants were all people starting MDR-TB treatment in seven DOTS-plus centres in the Kathmandu Valley, Nepal during January to December 2008. The primary outcome measure was cure, as internationally defined. Results: MDR-TB treatment caused extreme social, financial and employment hardship. Most patients had to move house and leave their job, and reported major stigmatisation. They were concerned about the long-term effects of their disease, and feared infecting others. In the resultant pilot intervention study, the two strategies appeared to improve treatment outcomes: cure rates for those receiving counselling, combined support and no support were 85%, 76% and 67% respectively. Compared with no support, the (adjusted) risk ratios of cure for those receiving counselling and receiving combined support were 1.2 (95% CI 1.0 to 1.6) and 1.2 (95% CI 0.9 to 1.6) respectively. The explanatory study demonstrated that patients valued both forms of support. Conclusions: MDR-TB patients are extremely vulnerable to stigma and extreme financial hardship. Provision of counselling and financial support may not only reduce their vulnerability, but also increase cure rates. National Tuberculosis Programmes should consider incorporating financial support and counselling into MDR-TB care: costs are low, and benefits high, especially since costs to society of incomplete treatment and potential for incurable TB are extremely high