Cudraflavone B induces human glioblastoma cells apoptosis via ER stress-induced autophagy.

BACKGROUND: Glioblastoma (GBM) is the most common malignant intracranial tumor with a low survival rate. However, only few drugs responsible for GBM therpies, hence new drug development for it is highly required. The natural product Cudraflavone B (CUB) has been reported to potentially kill a variety of tumor cells. Currently, its anit-cancer effect on GBM still remains unknown. Herein, we investigated whether CUB could affect the proliferation and apoptosis of GBM cells to show anti-GBM potential. RESULTS: CUB selectively inhibited cell viability and induced cell apoptosis by activating the endoplasmic reticulum stress (ER stress) related pathway, as well as harnessing the autophagy-related PI3K/mTOR/LC3B signaling pathway. Typical morphological changes of autophagy were also observed in CUB treated cells by microscope and scanning electron microscope (SEM) examination. 4-Phenylbutyric acid (4-PBA), an ER stress inhibitor, restored the CUB-caused alteration in signaling pathway and morphological change. CONCLUSIONS: Our finding suggests that CUB impaired cell growth and induced cell apoptosis of glioblastoma through ER stress and autophagy-related signaling pathways, and it might be an attractive drug for treatment of GBM.

Effect of spin polarization on electron acceleration in magnetized quantum plasma by a surface plasma wave.

The effect of spin-up and spin-down exchange interaction on electron acceleration by a surface plasma wave (SPW) propagating in magnetized quantum plasma has been studied. The SPW was excited over the metal-vacuum interface with maximum amplitude at the interface. The effective dielectric constant was evaluated, considering the effects of quantum Bohm potential, degenerate Fermi pressure, and electron spin. The externally applied magnetic field perturbed the densities of the oppositely spinning electrons, which resulted in spin polarization. The dispersion relation and energy exchange mechanism for the electron acceleration was built, incorporating the effects of spin polarization in the wave-plasma interaction. The energy gain was found to increase with the spin polarization.

Pattern, frequency and factors associated with inappropriate high dosing in chronic kidney disease patients at a tertiary care hospital in Pakistan.

BACKGROUND: Patients with chronic kidney diseases (CKD) are susceptible to the toxic drug effects if given unadjusted doses. Although Pakistan harbors a high burden of CKD patients, there is limited information available on the frequency, pattern and factors associated with unadjusted drug doses among CKD patients. METHODS: This cross-sectional study conducted at Sandeman Provincial Hospital, Quetta included 303 non-dialysis ambulatory CKD patients (glomerular filtration rate < 60 ml/min/1.73m2). The patients' data were collected through a purpose designed data collection form. The appropriateness of doses was checked against the renal drug handbook-2018, Kidney Disease Improving Global Outcomes guidelines, British National Formulary-2022, and manufacturer leaflets. Data were analysed by SPSS 23 and multiple binary logistic regression analysis was used to assess the factors associated with receiving inappropriate high doses. A p-value < 0.05 was considered statistically significant. RESULTS: The patients received a total of 2265 prescription lines, with a median of eight different drugs per patient (interquartile range: 6-9 drugs). A total of 34.5% (783/2265) drugs required dose adjustment. Of these, doses were not adjusted for 56.1% (440) drugs in 162 (53.4%) patients. The most common pharmacological class of drugs requiring dose adjustment were antibiotics (79.1%), followed by antidiabetics (59.2%), diuretics (57.0%), angiotensin converting enzyme inhibitors (56.9%), beta blockers (56.9%), analgesics (56.0%), angiotensin receptor blockers (55.2%), domperidone (53.9%) and antihyperlipidmics (46.1%). Patient's age of 41-60 (OR = 5.76) and > 60 years (OR = 9.49), hypertension (OR = 2.68), diabetes mellitus (OR = 3.47) and cardiovascular diseases (OR = 2.82) had statistically significant association (p-value < 0.05) with inappropriate high doses. CONCLUSION: The high frequency of inappropriate high doses suggests an important quality gap in medication dosing for patients with ND-CKD at the study site. Special attention should be paid to the drugs and patients with identified risk factors for receiving inappropriate high doses.

Prognostic accuracy of time to sputum culture conversion in predicting cure in extensively drug-resistant tuberculosis patients: a multicentre retrospective observational study.

BACKGROUND: There was a lack of information about prognostic accuracy of time to sputum culture conversion (SCC) in forecasting cure among extensively drug-resistant tuberculosis (XDR-TB) patients. Therefore, this study evaluated the prognostic accuracy of SCC at various time points in forecasting cure among XDR-TB patients. METHODS: This retrospective observational study included 355 eligible pulmonary XDR-TB patients treated at 27 centers in Pakistan between 01-05-2010 and 30-06-2017. The baseline and follow-up information of patients from treatment initiation until the end of treatment were retrieved from electronic nominal recording and reporting system. Time to SCC was analyzed by Kaplan-Meier method, and differences between groups were compared through log-rank test. Predictors of time to SCC and cure were respectively evaluated by multivariate Cox proportional hazards and binary logistic regression analyses. A p-value < 0.05 was considered statistically significant. RESULTS: A total of 226 (63.6%) and 146 (41.1%) patients respectively achieved SCC and cure. Median time to SCC was significantly shorter in patients who achieved cure, 3 months (95% confidence interval [CI]: 2.47-3.53), than those who did not (median: 10 months, 95% CI: 5.24-14.76) (p-value < 0.001, Log-rank test). Patient's age > 40 years (hazards ratio [HR] = 0.632, p-value = 0.004), baseline sputum grading of scanty, + 1 (HR = 0.511, p-value = 0.002), + 2, + 3 (HR = 0.523, p-value = 0.001) and use of high dose isoniazid (HR = 0.463, p-value = 0.004) were significantly associated with early SCC. Only SCC at 6 month of treatment had statistically significant association with cure (odds ratio = 15.603, p-value < 0.001). In predicting cure, the sensitivities of SCC at 2, 4 and 6 months were respectively 41.8% (95%CI: 33.7-50.2), 69.9% (95%CI: 61.7-77.2) and 84.9% (95%CI: 78.1-90.3), specificities were respectively, 82.8% (95%CI: 76.9-87.6), 74.6% (95%CI: 68.2-80.4) and 69.4% (95%CI: 62.6-75.5) and prognostic accuracies were respectively 65.9% (95%CI: 60.7-70.8), 72.7% (95%CI: 67.7-77.2) and 75.8% (95%CI: 71.0-80.1). CONCLUSION: In forecasting cure, SCC at month 6 of treatment performed better than SCC at 2 and 4 months. However, it would be too long for clinicians to wait for 6 months to decide about the regimen efficacy. Therefore, with somewhat comparable prognostic accuracy to that SCC at 6 month, using SCC at 4 month of treatment as a prognostic marker in predicting cure among XDR-TB patients can decrease the clinicians waiting time to decide about the regimen efficacy.

Evaluation of potential drug-drug interactions in cancer patients at a tertiary care hospital in Pakistan.

BACKGROUND: Despite harboring a high burden of cancer patients who are at high risk of potential drug-drug interactions (pDDIs), there is scarcity of published information about pDDIs in cancer patients from Pakistan. OBJECTIVE: To evaluate frequency, pattern, mechanism and factors associated with pDDIs in cancer patients treated at a tertiary care hospital in Pakistan. METHODS: In this cross-sectional analytical study, a total of 253 eligible ambulatory cancer patients treated at Center for Nuclear Medicine and Radiotherapy Hospital Quetta were evaluated for pDDIs using IBM Micromedex® Drug Interactions. SPSS (version 26) was used for conducting multivariate analysis to find factors associated with the presence pDDIs. A p-value <0.05 was considered statistically significant. RESULTS: A total of 141/253 (55.7%) patients were exposed to at-least one pDDI. A total of 251 pDDIs were noted with a median of one pDDI/per patient (interquartile range:1-2) Majority interactions were of major severity (72.9%), pharmacodynamic (49.8%) and had fair documentation level (64.1%). Anti-cancer drugs were involved in 73.0% pDDIs with doxorubicin as the most commonly involved (40.0%) anti-cancer followed by cyclophosphamide (27.6%) and cisplatin (13.5%). Potential cardiac adverse events made the bulk (33.8%) of predicted events. Receiving >2 anti-cancer (OR = 5.19, p-value = 0.001) and >6 ancillary drugs (OR = 4.16, p-value = 0.033) emerged as the risk factors of pDDIs. CONCLUSIONS: The prevalence of pDDIs was within the range reported in published literature. Solid medication review, availability of DDI detecting tools and clinical pharmacist, and paying special attention to the high-risk patients may reduce the frequency of pDDIs at the study site.

Antibiotic stewardship program in Pakistan: a multicenter qualitative study exploring medical doctors' knowledge, perception and practices.

BACKGROUND: The emerging threat of antibiotic resistance is growing exponentially and antibiotic stewardship programs are cornerstone to fight against this global threat. The study aimed to explore the knowledge, perspectives and practices of physicians regarding various aspects of antibiotic stewardship program including antibiotic stewardship activities, rational use of antibiotics, antibiotic resistance, prescribing practices and factors associated with these practices. METHODS: In this qualitative study, a total of 17 semi-structured, in-depth interviews with doctors of three tertiary care public sector hospitals in Bahawalpur and Rahim Yar Khan were conducted. The convenient sampling method was adopted to collect the data and the saturation point criterion was applied to determine the sample size. Thematic analysis approach was used to draw conclusions from the data. RESULTS: The analysis of data yielded five themes, 12 subthemes and 26 categories. The themes included, (i) perception about antibiotic use and antibiotic stewardship, (ii) antibiotic prescription practices, (iii) antibiotic resistance, (iv) limited strategies adopted by hospital administration to ensure quality and safe distribution of antibiotics, (v) implementation of antibiotic stewardship program: barriers, suggestion and future benefits. Doctors had misconceptions about the rational use of antibiotics. The perception regarding antibiotic stewardship programs was poor. Moreover, very few activities related to ASP existed. The participants gave many suggestions for successful implementation of ASP in order to reduce the burden of antibiotic resistance, including development of guidelines for the use of antibiotics, strict legislation regarding use of antibiotics, active participation of healthcare professionals and awareness program among general public about the use of antibiotics. CONCLUSION: This study concluded that poor knowledge of doctors regarding ASP, non-existence of antibiogram of hospital and lack of rules for the safe use of antibiotics were the main driving factors associated with irrational antibiotic prescription practices and development of AR.

High rate of successful treatment outcomes among childhood rifampicin/multidrug-resistant tuberculosis in Pakistan: a multicentre retrospective observational analysis.

BACKGROUND: There was a complete lack of information about the treatment outcomes of rifampicin/multidrug resistant (RR/MDR) childhood TB patients (age ≤ 14 years) from Pakistan, an MDR-TB 5th high burden country. Therefore, this study evaluated the socio-demographic characteristics, drug resistance pattern, treatment outcomes and factors associated with unsuccessful outcomes among childhood RR/MDR-TB patients in Pakistan. METHODS: This was a multicentre retrospective record review of all microbiologically confirmed childhood RR/MDR-TB patients (age ≤ 14 years) enrolled for treatment at seven units of programmatic management of drug-resistant TB (PMDT) in Pakistan. The baseline and follow-up information of enrolled participants from treatment initiation until the end of treatment were retrieved from electronic nominal recording and reporting system. World Health Organization (WHO) defined criterion was used for deciding treatment outcomes. The outcomes of "cured" and "treatment completed" were collectively grouped as successful, whereas "death", "treatment failure" and "lost to follow-up" were grouped together as unsuccessful outcomes. Multivariable binary logistic regression analysis was used to find factors associated with unsuccessful outcomes. A p-value < 0.05 reflected statistically significant findings. RESULTS: A total of 213 children RR/MDR-TB (84 RR and 129 MDR-TB) were included in the study. Majority of them were females (74%), belonged to the age group 10-14 years (82.2%) and suffered from pulmonary TB (85.9%). A notable proportion (37.1%) of patients had no history of previous TB treatment. Patients were resistant to a median of two drugs (interquartile range: 1-4) and 23% were resistant to any second line anti-TB drug. A total of 174 (81.7%) patients achieved successful treatment outcomes with 144 (67.6%) patients being cured and 30 (14.1%) declared treatment completed. Among the 39 (18.3%) patients with unsuccessful outcomes, 35 (16.4%) died and 4 (1.9%) experienced treatment failure. In multivariable analysis, the use of ethambutol had statistically significant negative association with unsuccessful outcomes (odds ratio = 0.36, p-value = 0.02). CONCLUSIONS: In this study, the WHO target of successful treatment outcomes (≥ 75%) among childhood RR/MDR-TB patients was achieved. The notable proportion of patients with no history of previous TB treatment (37.1%) and the disproportionately high number of female patients (74%) respectively stress for infection control measures and provision of early and high quality care for female drug susceptible TB patients.

Combination of metformin and cold atmospheric plasma induces glioma cell death to associate with c-Fos.

Glioma is the most common type of brain cancer. Chemotherapy combination with surgery and radiotherapy is a standard treatment for patients. Although there are many advances in glioma therapy, the prognosis of glioma patients has not significantly been improved over the past decades. Hence, there is still an urgent need to develop a new therapy to treat glioma. Cell viability was assessed by CellTiter Blue assay; flow cytometry (FCM) was used for detecting cell apoptosis; ROS detection was detected by ROS Assay; H2O2 detection was performed by hydrogen peroxide detection kits; real-time PCR and WB were used to determine gene expression. Using the glioma cell line U251 and U87, we investigated a possible combination inhibitory effect includes metformin and cold atmospheric plasma (CAP). The combination treatment showed a synergistic inhibitory effect on cell viability, significantly inducing cell apoptosis. Furthermore, we also found H2O2 produced by CAP has an important role in the synergistic inhibitory effect, eliminating H2O2 with catalase reversed the synergistic inhibitory effect. In addition, the transcript and protein levels of c-FOS were robustly increased after co-treated with metformin and CAP. Taken together, we propose that pre-treatment of glioma cells with metformin sensitize tumor cells to CAP, which may serve as a potential therapeutic strategy for glioma.

What impact does medicines shortages have on patients? A qualitative study exploring patients' experience and views of healthcare professionals.

BACKGROUND: The shortage of medicines represents a complex global phenomenon that triggers patient care and safety issues. The study was undertaken to explore the impact of medicines shortages on patients in Pakistan. The study also identified barriers which hinder the solutions of medicines shortages issue. METHODS: A qualitative study design was adopted and the data was collected in stages between July and September 2019using an in-depth interview approach. The purposive and convenient sampling strategy was used to recruit the study participants. Sample size was limited by using the saturation point criteria. All interviews were audio-recorded, transcribed verbatim, and analyzed using thematic analysis. RESULTS: A total of 35 stakeholders including 13 physicians, 12 pharmacists and 10 patients participated in the study. The findings of the study were classified into five key themes and seven subthemes. The five themes included, 'impact of medicine shortages on patients', 'patients' practices in response to medicine shortages', 'influence of medicines shortages on medical practice or pharmaceutical business', 'barriers to solutions for medicines shortages', and 'suggestions to assuage the impact of medicine shortages.'This study showed that the medicine shortages had significant clinical and financial impact on patients. Patients' opted for a number of risk-prone practices to avoid treatment disruption during shortages. An array of pharmaceutical market, medicines quality and patient related factors refrain physicians to switch from brand name medicine to generics and lead to ineffective management of medicines shortages. Promotion of generic prescription, implementation of punitive policies and proper patient consultation was advised to assuage the impact of medicine shortages on patients. CONCLUSION: The adverse clinical, economic and humanistic impact affirmed in this study demand the introduction of risk-management strategies for medicines shortages in hospital and community settings in accordance with the international standards. Promotion of effective patient counselling by the healthcare professionals to deter risk-prone practices associated with medicines shortages is mandatory.

Treatment Outcomes of Childhood Tuberculosis in Three Districts of Balochistan, Pakistan: Findings from a Retrospective Cohort Study.

BACKGROUND: This study aimed to evaluate treatment outcomes and factors associated unsuccessful outcomes among pediatric tuberculosis (TB) patients (age ≤14 years). METHODS: This was a retrospective cohort study conducted at three districts (Quetta, Zhob and Killa Abdullah) of Balochistan, Pakistan. All childhood TB patients enrolled for treatment at Bolan Medical Complex Hospital (BMCH) Quetta and District Headquarter Hospitals of Zhob and Killa Abdullah from 1 January 2016 to 31 December 2018 were included in the study and followed until their treatment outcomes were reported. Data were collected through a purpose developed standardized data collection form and analyzed by using SPSS 20. A p-value <0.05 was considered statistically significant. RESULTS: Out of 5152 TB patients enrolled at the study sites, 2184 (42.4%) were children. Among them, 1941 childhood TB patients had complete medical record were included in the study. Majority of the study participants were <5 years old (66.6%) and had pulmonary TB (PTB; 65%). A total of 45 (2.3%) patients were cured, 1680 (86.6%) completed treatment, 195 (10%) lost to follow-up, 15 (0.8%) died, 5 (0.3%) failed treatment and 1 (0.1%) was not evaluated for outcomes. In multivariate binary logistic regression analysis, treatment at BMCH Quetta (OR = 25.671, p-value < 0.001), rural residence (OR = 3.126, p-value < 0.001) and extra-PTB (OR = 1.619, p-value = 0.004) emerged as risk factors for unsuccessful outcomes. CONCLUSION: The study sites collectively reached the World Health Organization's target of treatment success (>85%). Lost to follow-up was the major reason for unsuccessful outcomes. Special attention to patients with identified risk factors for unsuccessful outcomes may improve outcomes further.

How medicines sales staff is responding to presumptive COVID-19 patients attending drug retail outlets: An exploratory qualitative study.

The objective of this qualitative study was to explore how the medicine sales staff responded to presumptive COVID-19 patients in Pakistan. The data were obtained from the medicine sales staff working at drug retail outlets of Bahawalpur, Punjab, Pakistan, through in-depth face-to-face interviews using a semi-structured interview guide. A two-step sampling strategy was used, including purposive and convenient sampling techniques. Sample size was determined by applying the saturation point criteria. A total of 17 interviews were audio-recorded, transcribed verbatim and analysed using the thematic analysis. Analysis of data yielded six themes and seven sub-themes. The themes included (1) knowledge about various aspects of COVID-19, (2) practices of sales staff in response to COVID-19 pandemic, (3) attitude of sales staff towards COVID-19 pandemic, (4) services offered to presumptive COVID-19 patients, (5) challenges encountered during pandemic and (6) suggestions to improve delivery of pharmacy services by sales staff. In Pakistan, non-pharmacist sales staff had superficial knowledge about COVID-19. Presumptive COVID-19 patients were provided with only basic pharmacy services. Professional training is advised among pharmacy sales staff as a short-term solution to improve their knowledge. As a long-term goal, the availability of pharmacists at drug retail outlets is warranted.

Visible light-conducting polymer nanocomposites as efficient photocatalysts for the treatment of organic pollutants in wastewater.

This review compiles recent advances and challenges on photocatalytic treatment of wastewater using nanoparticles, nanocomposites, and polymer nanocomposites as photocatalyst. The review provides an overview of the fundamental principles of photocatalytic treatment along the recent advances on photocatalytic treatment, especially on the modification strategies and operational conditions to enhance treatment efficiency and removal of recalcitrant organic contaminants. The different types of photocatalysts along the key factors influencing their performance are also critically discussed and recommendations for future research are provided.

Inter-estuarine and seasonal to decadal variations of heavy metal pollution in the Gulf of Cambay, India.

Toxic heavy metals adsorbed preferentially onto suspended sediments enter our food chain by bio-assimilation in coastal ocean organisms. To decipher metal pollution status in the Gulf of Cambay (food hub of India) under rising anthropogenic pressure, we present seasonal abundances of Ti, Cr, Co, Ni, Cu, Zn, Cd, and Pb in > 150 samples of suspended sediments (> 0.45 µm) collected in four seasons (2016-2017) from two large estuaries (Narmada and Tapi). The suspended sediments of both the estuaries generally show low heavy metal pollution (Igeo < 1). The hotspots of moderate-to-high pollution of Pb (Igeo < 4), Cd (Igeo < 3), and Zn (Igeo < 2) are found at salinity < 2, and those of Co (Igeo < 2) at salinity ~ 20-30 in the Tapi estuary during the non-monsoon seasons indicating their decoupled sources in Surat. The PLI values show no or little seasonality in the overall metal pollution status of both the estuaries. A comparison with the literature data suggests that suspended sediments efficiently capture active metal pollution in Indian estuaries. Furthermore, a recent decline (2004-2017) in estuarine metal pollution in the Gulf of Cambay found in this study could be due to enhanced organic matter supplies by enhanced urban sewage discharge and/or more trapping of contaminated riverine sediments upstream of the newly built large dam reservoirs counteracting the growth of anthropogenic metal inputs in the Narmada and Tapi watersheds. The data scarcity of heavy metal concentrations in suspended sediments limits reporting unambiguously the current pollution status of other major Indian estuaries.

A surface modifier enhances the performance of the all-inorganic CsPbI2Br perovskite solar cells with efficiencies approaching 15.

All-inorganic perovskite solar cells (PSCs) are attracting considerable attention due to their promising thermal stability, but their inferior power-conversion efficiencies (PCE) hinder their realistic application. Here, we propose an approach through surface modification based on methyl ammonium halide (MAX) for inorganic CsPbI2Br solar cells processed at a low temperature. The combined benefits of the introduced MAX modifier enable the boosting of the power conversion efficiency to 14.8% with an impressive FF of 82.2% in CsPbI2Br PSCs. Our experimental analyses coupled with optical modeling indicate that the incorporated MAX leads to an effective passivation of the surface traps originating from Pb2+ and I- ions in CsPbI2Br and simultaneously mediates the crystallization of CsPbI2Br with slightly enlarged grains and reduced numbers of structural defects and pinhole. As a result, the interfacial trap-assisted recombination is suppressed and the charge extraction is promoted. Mechanistically, we show that in the presence of MAX, the deep-level traps in the perovskites are passivated, leaving the energy of the trapping centers to become shallower. In this situation, the negative impacts of the traps on carrier transport and recombination are mitigated.

Comparison of cystatin C and creatinine-based estimated glomerular filtration rate equations among elderly chronic kidney disease patients attending a tertiary care hospital: A prospective cross-sectional study
.

BACKGROUND: Serum creatinine has been solely used in clinical practice to identify chronic kidney disease (CKD) staging in the elderly population. Serum cystatin C is believed to more accurately define the CKD staging and is also ratified as an endogenous biomarker by Kidney Disease Improving Global Outcomes (KDIGO) guidelines. MATERIAL AND METHODS: A total of 300 elderly Malay participants (age ≥ 65 years) with CKD, attending the Hospital University Sains Malaysia were included in the study. Demographic data and history were also recorded. Serum creatinine was assayed by Chemistry Analyzer Model Architect-C8000 (Jaffe method). While serum cystatin C was examined by Human cystatin C ELISA kit (Sigma-Aldrich) using Thermo Scientific Varioskan Flash ELISA reader. RESULTS: Out of 300 study participants, 169 (56.3%) were females. Mean age of patients was 67.6 ± 6.7 years. 64 male (64.6%) and 35 female (35.4%) patients were between 70 and 79 years. When estimated by MDRD equation, the prevalence of CKD stage 3 (defined as eGFR = 30 - 59 mL/min/1.73m2) was 27.7%, while based on CKD-EPIcr, CKD-EPIcys, and CKD-EPIcr-cys equations, it was 28%, 36.3%, and 36.3%, respectively. The prevalence of CKD stage 4 (defined as eGFR = 15 - 29 mL/min/1.73m2) when estimated by MDRD was 37.6%, whereas based on CKD-EPIcr, CKD-EPIcys, and CKD-EPIcr-cys equations, it was 36.3%, 46.4%, and 46.4%, respectively. CKD stage 5 (defined as eGFR < 15 mL/min/1.73m2) when estimated by the MDRD equation was 34.7%. While based on CKD-EPIcr, CKD-EPIcys, and CKD-EPIcr-cys equations, the prevalence of CKD stage 5 was 35.7%, 17.3%, and 17.3%, respectively. CONCLUSION: The staging of CKD is different between the creatinine- and cystatin C-based equations. Creatinine-based equations classify patients as having CKD stage 5 twice as often as cystatin C-based equations.

Chitosan modified Fe3O4/graphene oxide nanocomposite as a support for high yield and stable immobilization of cellulase: its application in the saccharification of microcrystalline cellulose.

In the present study, specialized methodology of utilizing novel nanobiocatalyst, chitosan coated magnetic graphene (Fe3O4/GO/CS), for efficacious immobilization of Trichoderma reesei cellulase, an important industrial enzyme was revealed. The cellulase was covalently immobilized onto the nanocomposite (NC) using covalent-glutaraldehyde coupling methodology. Successful immobilization of the cellulase with Fe3O4/GO/CS NC was affirmed by transmission electron microscopy, Fourier transform infrared spectroscopy and scanning electron microscopy. The nanobiocatalyst preparations exhibited significantly improved activity, retaining 78% of the initial activity as compared to its soluble counterpart. Immobilization of cellulase also highlighted significant broadening in pH, thermal and storage stability profiles. The kinetic properties of cellulase bound Fe3O4/GO/CS NC showed lower Km indicating increased affinity (1.87 times) of nanobioconjugate toward the substrate. Cellulase bound Fe3O4/GO/CS NC was able to maintain higher percentages of its primary activity after 8 repeated uses. This nanobioconjugate preparation proves to be industrially robust biocatalyst with enhanced nano-biocatalytic activity, stability and reusability attributes, which can be exploited for hydrolysis of microcrystalline cellulose providing increased amount of sugar compared to free cellulase.

Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis.

BACKGROUND: Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis. METHODS: In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment completion [success], failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic, or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration. FINDINGS: Of 12 030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died. Compared with failure or relapse, treatment success was positively associated with the use of linezolid (adjusted risk difference 0·15, 95% CI 0·11 to 0·18), levofloxacin (0·15, 0·13 to 0·18), carbapenems (0·14, 0·06 to 0·21), moxifloxacin (0·11, 0·08 to 0·14), bedaquiline (0·10, 0·05 to 0·14), and clofazimine (0·06, 0·01 to 0·10). There was a significant association between reduced mortality and use of linezolid (-0·20, -0·23 to -0·16), levofloxacin (-0·06, -0·09 to -0·04), moxifloxacin (-0·07, -0·10 to -0·04), or bedaquiline (-0·14, -0·19 to -0·10). Compared with regimens without any injectable drug, amikacin provided modest benefits, but kanamycin and capreomycin were associated with worse outcomes. The remaining drugs were associated with slight or no improvements in outcomes. Treatment outcomes were significantly worse for most drugs if they were used despite in-vitro resistance. The optimal number of effective drugs seemed to be five in the initial phase, and four in the continuation phase. In these adjusted analyses, heterogeneity, based on a simulated I2 method, was high for approximately half the estimates for specific drugs, although relatively low for number of drugs and durations analyses. INTERPRETATION: Although inferences are limited by the observational nature of these data, treatment outcomes were significantly better with use of linezolid, later generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for treatment of multidrug-resistant tuberculosis. These findings emphasise the need for trials to ascertain the optimal combination and duration of these drugs for treatment of this condition. FUNDING: American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.

Homozygous CHST11 mutation in chondrodysplasia, brachydactyly, overriding digits, clino-symphalangism and synpolydactyly.

BACKGROUND: Carbohydrate sulfotransferase 11 (CHST11) is a membrane protein of Golgi that catalyses the transfer of sulfate to position 4 of the N-acetylgalactosamine residues of chondroitin. Chondroitin sulfate is the predominant proteoglycan in cartilage, and its sulfation is important in the developing growth plate of cartilage. A homozygous deletion encompassing part of the gene and the embedded miRNA MIR3922 had been detected in a woman with hand/foot malformation and malignant lymphoproliferative disease. Chst11-deficient mouse has severe chondrodysplasia, congenital arthritis and neonatal lethality. We searched for the causative variant for the unusual combination of limb malformations with variable expressivity accompanied by skeletal defects in a consanguineous Pakistani kindred. METHODS: We performed detailed clinical investigations in family members. Homozygosity mapping using SNP genotype data was performed to map the disease locus and exome sequencing to identify the underlying molecular defect. RESULTS: The limb malformations include brachydactyly, overriding digits and clino-symphalangism in hands and feet and syndactyly and hexadactyly in feet. Skeletal defects include scoliosis, dislocated patellae and fibulae and pectus excavatum. The disease locus is mapped to a 1.6 Mb region at 12q23, harbouring a homozygous in-frame deletion of 15 nucleotides in CHST11. Novel variant c.467_481del (p.L156_N160del) is deduced to lead to the deletion of five evolutionarily highly conserved amino acids and predicted as damaging to protein by in silico analysis. Our findings confirm the crucial role of CHST11 in skeletal morphogenesis and show that CHST11 defects have variable manifestations that include a variety of limb malformations and skeletal defects.

Targeting of JAK-STAT Signaling in Breast Cancer: Therapeutic Strategies to Overcome Drug Resistance.

Rapidly emerging ground-breaking discoveries have provided near to complete resolution of breast cancer signaling landscape and scientists have mapped the knowledge gaps associated with proteins encoded by the human genome. Based on the insights gleaned from decades of research, it seems clear that ligands transmit distinct information through specific receptors that is processed into characteristically unique biological outputs. Advances in imaging, structural biology, proteomics and genome editing have helped us to gain new insights into JAK-STAT signaling and how alterations in this pathway contributed to development of breast cancer and metastatic spread. Data obtained through high-throughput technologies has started to shed light on signal-transducer complexes formed during JAK-STAT signaling. Pharmacologists and molecular biologists are focusing on the strategies to therapeutically target this pathway to overcome drug resistance associated with breast cancer.

Rapid detection of human blood in triatomines (kissing bugs) utilizing a lateral flow immunochromatographic assay - A pilot study.

OBJECTIVES: We tested a rapid and specific immunochromatographic assay (that detects human blood in forensic samples) to determine if human blood was present in triatomines and their fecal excreta. METHODS: We fed Triatoma rubida human blood (positive control) or mouse blood (negative control) and performed the assay on the abdominal contents and fecal excreta. Triatomine field specimens collected in and around human habitations and excreta were also tested. FINDINGS: The assay was positive in triatomines fed human blood (N = 5/5) and fecal excreta from bugs known to have ingested human blood (N = 5/5). Bugs feeding on mice (N = 15/15) and their fecal excreta (N = 8/8) were negative for human blood. Human blood was detected in 47% (N = 23/49) triatomines, representing six different species, collected in the field. MAIN CONCLUSIONS: The pilot study shows that this rapid and specific test may have applications in triatomine research. Further study is needed to determine the sensitivity of this assay compared to other well-established techniques, such as DNA- and proteomics-based methodologies and the assay's application in the field.