Role of Concomitant Internal Limiting Membrane (ILM) Peeling During Rhegmatogenous Retinal Detachment (RRD) Surgery in Preventing Postoperative Epiretinal Membrane (ERM) Formation.

OBJECTIVE: To investigate the role of concomitant Internal Limiting Membrane (ILM) peeling during surgery for macula off Rhegmatogenous Retinal Detachment (RRD) in preventing postoperative Epiretinal Membrane (ERM) formation; and its effect on the visual acuity. METHODS: This was a prospective, quasi-experimental study conducted from August 2018 to July 2019 at LRBT Tertiary Eye Care hospital, Karachi. Fifty-six patients with macula off RRD were divided into groups A (with ILM peeling) and B (without ILM peeling) via non-probability convenience sampling. All patients underwent standard 3 ports pars plana vitrectomy with silicon oil tamponade. In Group-A, ILM was stained using 0.5% ICG. Patients were evaluated clinically and by spectral domain optical coherence tomography (SD-OCT), pre- and post-operatively. Main outcomes recorded were best corrected visual acuity (BCVA) and occurrence of ERM on SD-OCT. RESULTS: There were 26 patients in Group-A and 30 patients in Group-B. At six months' follow-up, ERM had not developed in any case in Group-A compared to five patients (16.7%) in Group-B. There was no statistical difference in mean BCVA change from baseline. CONCLUSION: ILM peeling during vitrectomy for RRD prevents the formation of macular ERM post-operatively. This may reduce the need of a second vitrectomy. However, visual outcomes were comparable to the non-ILM peeling vitrectomy.

Achieving pro-poor growth and environmental sustainability agenda through information technologies: as right as rain.

The pro-poor growth and environmental sustainability are the twin agendas widely discussed in environmental science literature. The technology-embodied growth helps to attain both agendas through knowledge sharing and technology transfer, which trickle down to the poor income group and improve their living standards. Hence, the role of information and communication technologies (ICTs) is deemed crucial in boosting economic growth and is under deep consideration to establish its role in reducing poverty and environmental pollution. The current study examines the long-run relationship between ICTs, poverty reduction, and ecological degradation in Pakistan using time series data from 1975-2018. The short- and long-run parameter estimates were obtained through the Autoregressive Distributed Lag (ARDL) model for robust inferences. The results substantiate the inverted U-shaped Environmental Kuznets Curve relationship between income and emissions with a turning point at US$1000 in the short-run and US$800 in the long-run. The results confirmed the decisive intervention of ICTs factors in the poverty reduction, i.e., computer communications and mobile-telephone-broadband subscriptions support to reduce poverty incidence with the mediation of inbound FDI in a country. As far as income inequality is concerned, it shows that computer services support minimizing income inequality via a channel of high-technology exports in a country. The technology embodied emissions verified in the long-run, where mobile-telephone-broadband subscriptions increase carbon emissions. Finally, mobile-telephone-broadband subscriptions and inbound FDI both are significant contributors to amplify the country's economic growth. The results conclude that poverty reduction and environmental sustainability agenda are achieved by developing green ICT infrastructure in a country.

Characterization of CYP3A pharmacogenetic variation in American Indian and Alaska Native communities, targeting CYP3A4*1G allele function.

The frequencies of genetic variants in the CYP3A4 and CYP3A5 genes differ greatly across global populations, leading to profound differences in the metabolic activity of these enzymes and resulting drug metabolism rates, with important consequences for therapeutic safety and efficacy. Yet, the impact of genetic variants on enzyme activity are incompletely described, particularly in American Indian and Alaska Native (AIAN) populations. To characterize genetic variation in CYP3A4 and CYP3A5 and its effect on enzyme activity, we partnered with AIAN people living in two regions of Alaska: Yup'ik Alaska Native people living in the Yukon-Kuskokwim Delta region of rural southwest Alaska and AIAN people receiving care at the Southcentral Foundation in Anchorage, Alaska. We identified low frequencies of novel and known variation in CYP3A4 and CYP3A5, including low frequencies of the CYP3A4*1G and CYP3A5*1 variants, and linkage disequilibrium patterns that differed from those we previously identified in an American Indian population in western Montana. We also identified increased activity of the CYP3A4*1G allele in vitro and in vivo. We demonstrated that the CYP3A4*1G allele confers increased protein content in human lymphoblastoid cells and both increased protein content and increased activity in human liver microsomes. We confirmed enhanced CYP3A4-mediated 4ß-vitamin D hydroxylation activity in Yup'ik people with the CYP3A4*1G allele. AIAN people in Alaska and Montana who carry the CYP3A4*1G allele-coupled with low frequency of the functional CYP3A5*1 variant-may metabolize CYP3A substrates more rapidly than people with the reference CYP3A4 allele.

Prospective validation of the RAPID clinical risk prediction score in adult patients with pleural infection: the PILOT study.

BACKGROUND: Over 30% of adult patients with pleural infection either die and/or require surgery. There is no robust means of predicting at baseline presentation which patients will suffer a poor clinical outcome. A validated risk prediction score would allow early identification of high-risk patients, potentially directing more aggressive treatment thereafter. OBJECTIVES: To prospectively assess a previously described risk score (the RAPID (Renal (urea), Age, fluid Purulence, Infection source, Dietary (albumin)) score) in adults with pleural infection. METHODS: Prospective observational cohort study that recruited patients undergoing treatment for pleural infection. RAPID score and risk category were calculated at baseline presentation. The primary outcome was mortality at 3 months; secondary outcomes were mortality at 12 months, length of hospital stay, need for thoracic surgery, failure of medical treatment and lung function at 3 months. RESULTS: Mortality data were available in 542 out of 546 patients recruited (99.3%). Overall mortality was 10% at 3 months (54 out of 542) and 19% at 12 months (102 out of 542). The RAPID risk category predicted mortality at 3 months. Low-risk mortality (RAPID score 0-2): five out of 222 (2.3%, 95% CI 0.9 to 5.7%); medium-risk mortality (RAPID score 3-4): 21 out of 228 (9.2%, 95% CI 6.0 to 13.7%); and high-risk mortality (RAPID score 5-7): 27 out of 92 (29.3%, 95% CI 21.0 to 39.2%). C-statistics for the scores at 3 months and 12 months were 0.78 (95% CI 0.71-0.83) and 0.77 (95% CI 0.72-0.82), respectively. CONCLUSIONS: The RAPID score stratifies adults with pleural infection according to increasing risk of mortality and should inform future research directed at improving outcomes in this patient population.

Achieving environmental sustainability through information technology: "Digital Pakistan" initiative for green development.

The importance of information and communication technologies (ICTs) in environmental resource management opens a new debate for the policy makers in order to promote green technologies to mitigate high mass carbon emissions across the globe. "Digital Pakistan" initiative is taken by the government that aimed to use technology for country's social welfare, which further be enhance for achieving environmental sustainability over a time horizon. This study examined the long-run relationship between ICTs, energy demand, and carbon emissions in a context of Pakistan by using a time series data from 1975 to 2017. The results show that energy demand increases economic growth in the short-run while it decreases economic growth in the long-run. The country's economic growth substantially increases along with an increase in trade openness and mobile-telephone subscription (ICTs) in the short-run; however, the result is changed in the long-run due to increase in carbon emissions in a given time period. The results provoke that continued economic growth and ICT penetration substantially decreases energy demand, whereas urbanization increases energy demand in a country. The results show that variations in emissions associated with proportionate changes in ICTs penetration, economic growth, energy demand, and population growth. Human capital, trade openness, and energy demand are the significant drivers of ICT penetration in a country. The study concludes that the use of green technology is imperative for achieving long-term sustainable growth in a country.

Calix[4]arene Derivative-Modified Glassy Carbon Electrode: A New Sensing Platform for Rapid, Simultaneous, and Picomolar Detection of Zn(II), Pb(II), As(III), and Hg(II).

The glassy carbon electrode was fabricated with multifunctional bis-triazole-appended calix[4]arene and then used for the simultaneous detection of Zn(II), Pb(II), As(III), and Hg(II). Before applying the square-wave anodic stripping voltammetry, the sensitivity and precision of the modified electrode was assured by optimizing various conditions such as the modifier concentration, pH of the solution, deposition potential, accumulation time, and supporting electrolytes. The modified glassy carbon electrode was found to be responsive up to picomolar limits for the aforementioned heavy metal ions, which is a concentration limit much lower than the threshold level permitted by the World Health Organization. Importantly, the designed sensing platform showed anti-interference ability, good stability, repeatability, reproducibility, and applicability for the detection of multiple metal ions. The detection limits obtained for Zn(II), Pb(II), As(III), and Hg(II) are 66.3, 14.6, 71.9, and 28.9 pM, respectively.

Resistance to leukocytes ties benefits of quorum sensing dysfunctionality to biofilm infection.

Social interactions play an increasingly recognized key role in bacterial physiology1. One of the best studied is quorum sensing (QS), a mechanism by which bacteria sense and respond to the status of cell density2. While QS is generally deemed crucial for bacterial survival, QS-dysfunctional mutants frequently arise in in vitro culture. This has been explained by the fitness cost an individual mutant, a 'quorum cheater', saves at the expense of the community3. QS mutants are also often isolated from biofilm-associated infections, including cystic fibrosis lung infection4, as well as medical device infection and associated bacteraemia5-7. However, despite the frequently proposed use of QS blockers to control virulence8, the mechanisms underlying QS dysfunctionality during infection have remained poorly understood. Here, we show that in the major human pathogen Staphylococcus aureus, quorum cheaters arise exclusively in biofilm infection, while in non-biofilm-associated infection there is a high selective pressure to maintain QS control. We demonstrate that this infection-type dependence is due to QS-dysfunctional bacteria having a significant survival advantage in biofilm infection because they form dense and enlarged biofilms that provide resistance to phagocyte attacks. Our results link the benefit of QS-dysfunctional mutants in vivo to biofilm-mediated immune evasion, thus to mechanisms that are specific to the in vivo setting. Our findings explain why QS mutants are frequently isolated from biofilm-associated infections and provide guidance for the therapeutic application of QS blockers.

VKORC1 and Novel CYP2C9 Variation Predict Warfarin Response in Alaska Native and American Indian People.

Alaska Native and American Indian (AN/AI) people have unique pharmacogene variation that may affect warfarin disposition and therapeutic response. We performed targeted genotyping for cytochrome P450 (CYP)2C9, vitamin K epoxide oxidase reductase complex subunit 1 (VKORC1), CYP4F2, CYP4F11, and gamma-glutamyl carboxylase (GGCX) variants in AN/AI people receiving warfarin. The primary outcome was stable warfarin dose, defined as one dose, and associated international normalized ratio within the target range, at least 6 months after starting therapy, with two matching doses at least 2 weeks apart. Genotype-phenotype relationships were assessed by multivariate regression analysis, adjusted for self-reported heritage, age, gender, and concurrent statin use. VKORC1 genotype explained 34% of dose variability, with VKORC1 -1639G>A and 1173C>T associated with a 1.7 mg/day (P = 1.4e-05) dose reduction. Additionally, CYP2C9 N218I was suggestively significant (P = 0.077), with heterozygotes requiring 1.1 mg/day less than reference individuals. Self-reported heritage was significantly associated with dose, largely driven by differences in the diagnostic VKORC1 allele frequencies among AN/AI people.

Cytochrome P450 Genetic Variation Associated with Tamoxifen Biotransformation in American Indian and Alaska Native People.

Despite evidence that pharmacogenetics can improve tamoxifen pharmacotherapy, there are few studies with American Indian and Alaska Native (AIAN) people. We examined variation in cytochrome P450 (CYP) genes (CYP2D6, CYP3A4, CYP3A5, and CYP2C9) and tamoxifen biotransformation in AIAN patients with breast cancer (n = 42) from the Southcentral Foundation in Alaska and the Confederated Salish and Kootenai Tribes in Montana. We tested for associations between CYP diplotypes and plasma concentrations of tamoxifen and metabolites. Only the CYP2D6 variation was significantly associated with concentrations of endoxifen (P = 0.0008) and 4-hydroxytamoxifen (P = 0.0074), tamoxifen's principal active metabolites, as well as key metabolic ratios. The CYP2D6 was also the most significant predictor of active metabolites and metabolic ratios in a multivariate regression model, including all four genes as predictors, with minor roles for other CYP genes. In AIAN populations, CYP2D6 is the largest contributor to tamoxifen bioactivation, illustrating the importance of validating pharmacogenetic testing for therapy optimization in an understudied population.

Synthesis and characterisation of calix[4]arene based bis(triazole)-bis(hexahydroquinoline): Probing highly selective fluorescence quenching towards mercury (Hg2+) analyte.

In the present study, we are reporting the synthesis of a triazoles incorporated fluorescent hexahydroquinoline appended calix[4]arene 7 and its highly selective optical recognition ability towards Hg2+. The optical sensor 7 was synthesized via two different synthetic pathways and unambiguously characterized by mass spectrometry and NMR spectroscopy. The stoichiometric ratio between 7 and Hg2+ was determined as 1:1 based on Job's plot and ESI-MS analysis. The chemosensor 7 selectively recognized Hg2+ in the presence of competitive cations such as Cu2+, Cu1+, Co3+, Ni2+, Ag1+, Fe2+, Fe3+, Cr3+, Pb2+, Cd2+, Zn2+, Sn2+, Ti4+, Sb3+, In3+, Ba2+, Ca2+, and K1+. The limit of detection (LOD) was established as 0.5 µM on spectrofluorimetric analysis. According to world health organization (WHO) in guidelines for drinking-water quality, the mercury level in natural occurring ground and surface water is about ∼0.5 µM (µg/L). The supra molecule 7 with LOD (0.5 µM) could potentially serve effective receptors for Hg2+ cation. The probe 7 was applied effectively for detection of Hg2+ in real water samples (i.e. tap and deionized water), spiked with Hg2+ (10 µM) solution. Moreover, the compound 7 showed non-toxicity during cytotoxic assay against human B cells as they retain their morphology. The supramolecule 7 in living cells showed selectivity towards Hg2+ in cytotoxic assay with T lymphocytes, evident by morphological changes observed via AFM analysis.

Synthesis of High Molecular Weight Polyester Using in Situ Drying Method and Assessment of Water Vapor and Oxygen Barrier Properties.

The preparation of renewable polyesters with good barrier properties is highly desirable for the packaging industry. Herein we report the synthesis of high molecular weight polyesters via an innovative use of an in situ drying agent approach and the barrier properties of the films formed from these polyesters. High number average molecular weight (Mn) semiaromatic polyesters (PEs) were synthesized via alternating ring-opening copolymerization (ROCOP) of phthalic anhydride (PA) and cyclohexene oxide (CHO) using a salen chromium(III) complex in the presence of 4-(dimethylamino)pyridine (DMAP) cocatalyst. The use of a calcium hydride (drying agent) was found to enhance the number Mn of the synthesized PEs, which reached up to 31.2 ku. To test the barrier properties, PE films were prepared by solvent casting approach and their barrier properties were tested in comparison poly(lactic acid) films. The PE films showed significantly improved water vapor and oxygen barrier properties compared to the commercial poly(lactic acid) (PLA) film that suggests the potential use of these PEs in in the food packaging industry.

Synthesis, characterization and Cu(2+) triggered selective fluorescence quenching of Bis-calix[4]arene tetra-triazole macrocycle.

A novel fluorescent bis-calix[4]arene macrocycle 9 incorporating metal-binding pockets was successfully prepared. The structure of macrocycle 9 and its precursors were characterized via EI-MS, MALDI-TOF-MS, ESI-MS, (1)H NMR, (13)CNMR, 2D NMR, and X-ray crystallography. The macrocycle 9 displayed selective fluorescence quenching after interacting with Cu(2+) in the presence competing metal cations including Mg(2+), Ca(2+), Ba(2+), Ag(+), Zn(2+), Ti(4+),Cd(2+), Hg(2+), Pb(2+), In(3+), La(3+), Cr(3+), Ni(2+), Sb(3+), V(5+), Fe(3+), Co(2+), Sn(2+), Sn(2+), and Tl(+). The Cu(2+) limit of detection was found to be 40 nM much lower than its threshold level (∼ 20 µM) in drinking water permitted by the U.S Environmental Protection Agency (EPA). Furthermore, drinking water samples from Karachi University (Pakistan) spiked with Cu(2+) were analysed with the sensing system and the results showed an excellent agreement with the fluorescence quenching phenomenon of macrocycle 9 examined in deionized water. Importantly, the chemosensor 9 could be used to detect Cu(2+) in living cells.

Visual outcome of 25-gauge microincision vitrectomy surgery in diabetic vitreous haemorrhage.

OBJECTIVE: To assess the visual outcome and complications of 25-gauge micro incision vitrectomy surgery (MIVS) in diabetic vitreous haemorrhage. METHODS: This Quasi Experimental study was conducted at LRBT, Tertiary eye care hospital Karachi, from February 2012 to January 2013. Sixty eyes of sixty patients with uncontrolled type II diabetes mellitus (DM) were included. There were 43 (71.7%) males and 17 (28.3%) females. Age range was 40 - 60 years. All randomly selected patients underwent 25-gauge sutureless micro incision vitrectomy surgery for diabetic vitreous haemorrhage. Main outcomes measured were best corrected visual acuity (BCVA) assessed with logMAR and post-operative complications. Follow ups were at one day, one week, one month, three months and six months post-operatively. RESULT: Best corrected visual acuity (BCVA) gradually improved in majority of subjects in each subsequent follow up visit. Preoperative visual acuity was 1.023 ±0.226 logMAR, which was improved after final follow up to 0.457±0.256 and P-value was < 0.001. Five patients developed recurrent vitreous haemorrhage during study period, one patient developed cataract (1.7%), one (1.7%) had ocular hypotony defined as intraocular pressure < 5 mmHg and one (1.7%) developed endophthalmitis. CONCLUSION: 25-gauge micro incision vitrectomy surgery (MIVS) is an effective sutureless parsplana vitrectomy surgery which has good visual outcome in diabetic vitreous haemorrhage with minimum manageable complications.

SARM1, Not MyD88, Mediates TLR7/TLR9-Induced Apoptosis in Neurons.

Neuronal apoptosis is a key aspect of many different neurologic diseases, but the mechanisms remain unresolved. Recent studies have suggested a mechanism of innate immune-induced neuronal apoptosis through the stimulation of endosomal TLRs in neurons. TLRs are stimulated both by pathogen-associated molecular patterns as well as by damage-associated molecular patterns, including microRNAs released by damaged neurons. In the present study, we identified the mechanism responsible for TLR7/TLR9-mediated neuronal apoptosis. TLR-induced apoptosis required endosomal localization of TLRs but was independent of MyD88 signaling. Instead, apoptosis required the TLR adaptor molecule SARM1, which localized to the mitochondria following TLR activation and was associated with mitochondrial accumulation in neurites. Deficiency in SARM1 inhibited both mitochondrial accumulation in neurites and TLR-induced apoptosis. These studies identify a non-MyD88 pathway of TLR7/ TLR9 signaling in neurons and provide a mechanism for how innate immune responses in the CNS directly induce neuronal damage.

Variation in genes controlling warfarin disposition and response in American Indian and Alaska Native people: CYP2C9, VKORC1, CYP4F2, CYP4F11, GGCX.

OBJECTIVES: Pharmacogenetic testing is projected to improve health outcomes and reduce the cost of care by increasing therapeutic efficacy and minimizing drug toxicity. American Indian and Alaska Native (AI/AN) people historically have been excluded from pharmacogenetic research and its potential benefits, a deficiency we sought to address. The vitamin K antagonist warfarin is prescribed for prevention of thromboembolic events, although its narrow therapeutic index and wide interindividual variability necessitate close monitoring of drug response. Therefore, we were interested in variation in CYP2C9, VKORC1, CYP4F2, CYP4F11, and GGCX, which encode enzymes important for the activity of warfarin and synthesis of vitamin K-dependent blood clotting factors. METHODS: We resequenced these genes in 188 AI/AN people in partnership with Southcentral Foundation in Anchorage, Alaska and 94 Yup'ik people living in the Yukon-Kuskokwim Delta of southwest Alaska to identify known or novel function-disrupting variation. We conducted genotyping for specific single nucleotide polymorphisms in larger cohorts of each study population (380 and 350, respectively). RESULTS: We identified high frequencies of the lower-warfarin dose VKORC1 haplotype (-1639G>A and 1173C>T) and the higher-warfarin dose CYP4F2*3 variant. We also identified two relatively common, novel, and potentially function-disrupting variants in CYP2C9 (M1L and N218I), which, along with CYP2C9*3, CYP2C9*2, and CYP2C9*29, predict that a significant proportion of AI/AN people will have decreased CYP2C9 activity. CONCLUSION: Overall, we predict a lower average warfarin dose requirement in AI/AN populations in Alaska than that seen in non-AI/AN populations of the USA, a finding consistent with clinical experience in Alaska.

Investigational therapies targeting quorum-sensing for the treatment of Staphylococcus aureus infections.

INTRODUCTION: Antibiotic resistance is a serious global health concern for developed and developing nations. MRSA represents a particularly severe public health threat that is associated with high morbidity and mortality. The lack of novel antibiotics has led scientists to explore therapies targeting bacterial virulence mechanisms and virulence regulators, including those controlling cell-cell communication. AREAS COVERED: The authors discuss the role of quorum-sensing in Staphylococcus aureus infections and components of the system that are being targeted using novel investigational drugs. In particular, the authors examine the role of the accessory gene regulator (Agr) system in virulence regulation of S. aureus pathogenesis. Finally, the authors present and compare natural and synthetic compounds that have been found to interfere with Agr functionality. EXPERT OPINION: There is a great need to develop new therapeutic methods to combat S. aureus infections. These include anti-virulence therapies that target key global regulators involved with the establishment and propagation of infection. Several molecules have been found to interfere with S. aureus virulence regulation, especially those targeting the Agr quorum-sensing signaling molecule. These preliminary findings warrant further investigation and validation, with the goal of refining a compound that has broad-spectrum inhibitory effects on most S. aureus strains and Agr subtypes.

Phytochemicals, in vitro antioxidant, total phenolic contents and phytotoxic activity of Cornus macrophylla Wall bark collected from the North-West of Pakistan.

Plants are one of the precious creatures of Allah, producing a verity of useful bioactive compounds having definite pharmacological actions on human body. Keeping in view this idea, the methanolic extract from the bark of Cornus macrophylla was investigated for phytochemicals, antioxidant, total phenolic conte nts (TPC) and phytotoxic activities. Phytochemical analysis of Cornus macrophylla revealed the presence of tannins, anthraquinones, glycosides, reducing sugar, saponins and flavonoids. The percent free radicals scavenging potential of DPPH at 20, 40, 60, 80 and 100µg/ml was 72.69%, 73.32%, 73.51, 73.83% and 74.33% respectively and were compared to ascorbic acid (84.6%, 92.83%, 95.36%, 96.40% and 98.03%), gallic acid (85.49%, 92.47%, 95.14%, 98.22% and 98.03%) and quercetin (95.35%, 96.30%, 97.16%, 98.02% and 98.28%) as standards. The IC(50) value of Cornus macrophylla was 14.5/µg/ml. The TPC of the methanolic bark extract was 2.916 mg gallic acid equivalents/g of extract. The extract displyed excellent phytotoxic activity against the tested plant Lemna minor and inhibited the growth at 1000 µg/ml. Our findings revealed that the crude methanolic extract of Cornus macrophylla is a potential source of natural antioxidants and herbicidal.