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Objective: Our study aims to assess the frequency of self-medication in elderly people of Karachi, identify its reasons and associated risk factors. Study Design & Setting: This cross-sectional study was conducted in waiting areas of OPDs at Liaquat National hospital and its outreach centers. Methodology: Study duration was June-December, 2021. We approached all patients and aged 60 years and above. After taking written informed consent, targeted population was interviewed to find out self-medication performed within last three months and its reason and causes. Participants’ demographics, symptoms for which self-medication was performed, different type of medications used, reasons of opting self-medication and different approaches for dose adjustment were also investigated. Data was recorded by a pre-designed questionnaire. Data was analyzed using SPSS version 21. Result: Out of 200 elderly included in the study, 87% of them reported self-medication in a 3-month recall period. Pain (63.8%), fever (56.9%), headache (50%), cough, and cold (37.4%) were the most common symptoms. Pain killers (81.6%), fever-reducing drugs (58%) and cough syrup (39.1%) were the top three medicines used for self-medication. One-fifth of the respondents reported self-medication of antibiotics. Top three frequent reasons for self-medication were convenience (99.4%), disease of mild nature (85.1%) and for quick relief of symptoms (78.7%). None of the patient’s demographic factors were found to be associated with self-medication practice. Conclusion: Self-medication is a highly prevalent practice in elderly people of Karachi including non-prescribed usage of antibiotics. Major reforms in primary health care are needed to address this growing problem

Copyright © 2022 The Author(s). This article foregrounds religious minority youths’ subjective experiences of citizenship education in Pakistan to reflect on the relationship between educational curricula and religious exclusion. Drawing on narrative interviews with Hindu, Sikh, and Christian youth in the Punjab province, we demonstrate how sectarian constructions of national history and the paucity of positive representation in the curriculum inflict routinized forms of violence on minority youth and create an environment where anti-minority discriminations and prejudices can be justified. Youths’ narratives also reveal how they mobilize available institutional mechanisms to challenge these routine forms of violence and reinforce their commitment to an inclusive Pakistani identity. Reforms in citizenship education curricula are therefore urgently needed to address these concerns and promote an inclusive Pakistani identity. We situate our findings both in the historical context of contemporary Pakistan and the wider region of South Asia which has witnessed a rapid growth in exclusionary religious nationalisms.

Aberrant ocular angiogenesis can underpin vision loss in leading causes of blindness, including neovascular age-related macular degeneration and proliferative diabetic retinopathy. Current pharmacological interventions require repeated invasive administrations, may lack efficacy and are associated with poor patient compliance and tachyphylaxis. Vitamin D has de novo anti-angiogenic properties. Here, our aim was to validate the ocular anti-angiogenic activity of biologically active vitamin D, calcitriol, and selected vitamin D analogue, 22-oxacalcitriol. Calcitriol induced a significant reduction in ex vivo mouse choroidal fragment sprouting. Viability studies in a human RPE cell line suggested non-calcemic vitamin D analogues including 22-oxacalcitriol have less off-target anti-proliferative activity compared to calcitriol and other analogues. Thereafter, the anti-angiogenic activity of 22-oxacalcitriol was demonstrated in an ex vivo mouse choroidal fragment sprouting assay. In zebrafish larvae, 22-oxacalcitriol was found to be anti-angiogenic, inducing a dose-dependent reduction in choriocapillaris development. Subcutaneously administered calcitriol failed to attenuate mouse retinal vasculature development. However, calcitriol and 22-oxacalcitriol administered intraperitoneally, significantly attenuated lesion volume in the laser-induced choroidal neovascularisation mouse model. In summary, calcitriol and 22-oxacalcitriol attenuate ex vivo and in vivo choroidal vasculature angiogenesis. Therefore, vitamin D may have potential as an interventional treatment for ophthalmic neovascular indications. Funding agencies: Health Research Board, HRB-POR-2013-390, Irish Research Council, GOIPG/2015/2061, NIH/NEI R01EY025641, Retina Research Foundation, The foundation Jeanssons Stiftelser, The Magnus Bergvall foundation, and The Swedish Eye foundation.

Purpose To explore whether the Rho protein is involved in the radioresistance of colorectal cancer and investigate the underlying mechanisms. Methods and Materials Rho GTPase expression was measured after radiation treatment in colon cancer cells. RhoB knockout cell lines were established using the CRISPR/Cas9 system. In vitro assays and zebrafish embryos were used for analyzing radiosensitivity and invasive ability. Mass cytometry was used to detect RhoB downstream signaling factors. RhoB and Forkhead box M1 (FOXM1) expression were detected by immunohistochemistry in rectal cancer patients who participated in a radiation therapy trial. Results RhoB expression was related to radiation resistance. Complete depletion of the RhoB protein increased radiosensitivity and impaired radiation-enhanced metastatic potential in vitro and in zebrafish models. Probing signaling using mass cytometry–based single-cell analysis showed that the Akt phosphorylation level was inhibited by RhoB depletion after radiation. FOXM1 was downregulated in RhoB knockout cells, and the inhibition of FOXM1 led to lower survival rates and attenuated migration and invasion abilities of the cells after radiation. In the patients who underwent radiation therapy, RhoB overexpression was related to high FOXM1, late Tumor, Node, Metastasis stage, high distant recurrence, and poor survival independent of other clinical factors. Conclusions RhoB plays a critical role in radioresistance of colorectal cancer through Akt and FOXM1 pathways.

Most subsurface interpreters think of velocity as the most underutilized and overabused of all the geophysical parameters in oil and gas exploration. Nevertheless, velocity is the connection between time and depth, between milliseconds and feet, between timing lines and drill stem. We normally use velocities to stack seismic data, to migrate seismic data, and to convert time-recorded seismic sections to depth sections and time maps to depth maps. We also use velocities in more sophisticated ways, such as attempting to predict porosity, geologic age, lithology, fracturing, fluid content, geopressure, and even drill-bit wear. Velocity data contain an enormous amount of information.

For a successful exploration and field development project, good seismic-to-well ties and reliable time-to-depth conversion are essential. In exploration and production, our well data, production data, and geological targets are in the depth domain, but seismic reflections from subsurface rocks and geological structures are recorded in two-way travel time. The seismic data is also processed and mostly interpreted in the time domain, which is fast and good enough for many subsurface interpretation scenarios. But converting seismic reflection data from time domain to depth domain will enhance the integration of the seismic asset with geologic, petrophysical, and production data.

When we have well data (logs) and seismic data, we can correlate the two data sets to know how the sands and shales in the well data relate to peaks and troughs on the seismic section. For example, if we have a well and the top of the sand is at a setting depth of 6350 m, on the seismic section/line, we will know where the well is placed and know what events (peak or trough) on the seismic correspond to the top of the sand that we see on the well log. The top of the sand in the well log could either be in feet or meters, while the seismic is in two-way travel time, either in milliseconds or seconds. Thus well-ties are where and when one compares seismic data at a well location with well log data from the well.

The aim of study was to synthesize 1-indanyl isoniazid and sixteen other hydrazide Schiff base derivatives from 1-indanone. All synthesized derivatives were screened for the inhibitory activity against Mycobacterium tuberculosis on three Mycobacterial strains ATCC H37Rv, known INH-sensitive (INH-S) and INH-resistant strains (INH-R) by proportion method. The derivatives were characterized using different spectroscopic techniques such as UV-Visible, FTIR

Objectives Tuberculosis (TB) is a major public health concern and the basis of successful anti tuberculosis treatment (ATT) rests on the complete eradication of live bacilli from the patients. Keeping in view, this study was conducted to detect the live TB bacilli on Lowenstein Jensen culture media among exit cases of TB who were declared successfully treated, either cured or treatment completed. Methods This cross-sectional study was conducted in all across Pakistan. 58 active TB DOTS centers were selected. Sample size of 3355 TB cases were equally distributed in all DOTS facilities. A detailed questionnaire was developed to record the information from TB DOTS and patients. After successful treatment, the sputum was taken from TB cases and examined for the detection of live bacilli on L-J culture. Results 3355 TB cases were enrolled in the study. Male to female proportion was 1704 (50.9%) and 1651 (49.2%).Initially, 1993 (59.4%) cases were cured and 1362 (40.6%) were declared as treatment completed case. At exit, 324 (9.65%) cases were again ZN smear positive and 328 (9.77%) were positive on L-J culture after declared successfully treated for TB. Conclusions For the eradication of live TB bacilli, all the TB cases should be subjected for L-J culture at the end of ATT.

PURPOSE. Familial exudative vitreoretinopathy (FEVR) is an inherited retinal disease in which the retinal vasculature is affected. Patients with FEVR typically lack or have abnormal vasculature in the peripheral retina, the outcome of which can range from mild visual impairment to complete blindness. A missense mutation (p.His455Tyr) in ZNF408 was identified in an autosomal dominant FEVR family. Little, however, is known about the molecular role of ZNF408 and how its defect leads to the clinical features of FEVR. METHODS. Using CRISPR/Cas9 technology, two homozygous mutant zebrafish models with truncated znf408 were generated, as well as one heterozygous and one homozygous missense znf408 model in which the human p.His455Tyr mutation is mimicked. RESULTS. Intriguingly, all three znf408-mutant zebrafish strains demonstrated progressive retinal vascular pathology, initially characterized by a deficient hyaloid vessel development at 5 days postfertilization (dpf) leading to vascular insufficiency in the retina. The generation of stable mutant lines allowed long-term follow up studies, which showed ectopic retinal vascular hyper-sprouting at 90 dpf and extensive vascular leakage at 180 dpf. CONCLUSIONS. Together, our data demonstrate an important role for znf408 in the development and maintenance of the vascular system within the retina. Funding Agencies|Radboudumc PhD grant; Svenska Sallskapet for Medicinsk Forskning; Linkoping University; Loo och Hans Ostermans Stiftelse; Eva och Oscar Ahrens Stiftelse; Stiftelsen Sigurd och Elsa Goljes Minne; Magnus Bergvalls Stiftelse; Ogonfonden; Jeanssons Stiftelser; VetenskapsradetSwedish Research Council

Optical and magnetic features of the A 2 V 2 O 2 ( A = F e and C o ) compounds are explored. Density functional theory (DFT) within a framework of FPLAPW (full-potential linearized augmented plane wave) method, as well as generalized gradient approximation plus the Hubbard parameter (GGA+U) and Hubbard on-site Coulomb interaction corrections are applied. U is evaluated assuming constraint generalized gradient approximation for transition metals Fe/Co and V. The calculated band structures for the Fe doped compounds demonstrate the metallic nature while for the Co doped we observe half metallicity possessing 100% spin polarization in the vicinity of the Fermi level. The influence of Fe/Co and V magnetic moment (μ B ) on the electronic, magnetic and optical features is explored in details additionally. The optical constants reveal the strong response for A 2 V 2 O 2 ( A = F e and C o ) in the IR (infra-red region) and UV (Ultra Violet) regions.

The purpose of this project was to evaluate the pattern of transmission in patients suffering from Multidrug resistant (MDR) Tuberculosis by assessing their contact information. Data were obtained and analyzed from 164 individuals suffering from MDR TB. Records were scanned to evaluate the presence ofa close contact with known history of Tuberculosis. Tabulations and analysis were performed in Microsoft Excel® and online calculators. Analysis of contact data showed that only 36% of the patients had a close contact with a known Tuberculosis patient. Chi-square test did not show any association between history ofpresence of a contact and the patients’ gender (p>0.5). Among the cases with established exposure with a TB patient among close contacts, 17.5% females and 12.5% males reported exposure with a contact outside the close family. Majority of patients were unaware of the presence of a known contact in their vicinity. There was no association between knowledge about exposure and patients’ gender. The study shows that efforts of active case finding should be employed to find the hidden cases of Tuberculosis in the society to stop the spread by those patients, who are unaware of their disease.

Corneal neovascularization is a sight-threatening condition caused by angiogenesis in the normally avascular cornea. Neovascularization of the cornea is often associated with an inflammatory response, thus targeting VEGF-A alone yields only a limited efficacy. The NF-kappa B signaling pathway plays important roles in inflammation and angiogenesis. Here, we study consequences of the inhibition of NF-kappa B activation through selective blockade of the IKK complex I kappa B kinase beta (IKK2) using the compound IMD0354, focusing on the effects of inflammation and pathological angiogenesis in the cornea. In vitro, IMD0354 treatment diminished HUVEC migration and tube formation without an increase in cell death and arrested rat aortic ring sprouting. In HUVEC, the IMD0354 treatment caused a dose-dependent reduction in VEGF-A expression, suppressed TNF alpha-stimulated expression of chemokines CCL2 and CXCL5, and diminished actin filament fibers and cell filopodia formation. In developing zebrafish embryos, IMD0354 treatment reduced expression of Vegf-a and disrupted retinal angiogenesis. In inflammation-induced angiogenesis in the rat cornea, systemic selective IKK2 inhibition decreased inflammatory cell invasion, suppressed CCL2, CXCL5, Cxcr2, and TNF-alpha expression and exhibited anti-angiogenic effects such as reduced limbal vessel dilation, reduced VEGF-A expression and reduced angiogenic sprouting, without noticeable toxic effect. In summary, targeting NF-kappa B by selective IKK2 inhibition dampened the inflammatory and angiogenic responses in vivo by modulating the endothelial cell expression profile and motility, thus indicating an important role of NF-kappa B signaling in the development of pathologic corneal neovascularization. Funding Agencies|Swedish Research Council [2012-2472]; Swedish Foundation Stiftelsen Synframjandets Forskningsfond/Ogonfonden; Svenska Sallskapet for Medicinsk Forskning; Linkoping Universitet; Jeanssons Stiftelser

Hypoxia-induced metabolic pathways are excellent anti-tumor targets as these are specifically but broadly activated even under normoxia in cancer. However, these pathological metabolic profiles are often poorly recapitulated in vitro, and developing new drugs that target these tumor-specific metabolic enzymes therefore require in vivo models, even from an early stage. Screening of drug candidates or cell/PDX model libraries using zebrafish tumor xenograft (ZTX) models has become an attractive alternative to mice for fast assessment of drug efficacy in a variety of indications in vivo, but traditionally such models have not allowed for testing drugs that target hypoxia-induced metabolic pathways. Controlling the extent and duration of intratumor hypoxia in vivo has been done by mixing nitrogen gas directly into the water surrounding the larvae, and these systems have therefore not been amenable for high-throughput screening purposes. In order to advance the use of ZTX technologies and allow screening of drugs targeting hypoxia-induced metabolic pathways, a new, high-throughput platform for controlling hypoxia in zebrafish larvae is needed. Here we demonstrate the development of a ZTX platform in which hypoxia-induced pathophysiological changes in the tumor microenvironment are evaluated, and up-regulation of relevant drug targets are coupled to cell- and drug-screening capabilities. The system that we have developed here allows for screening of hundreds of tumor-bearing larvae in many different experimental groups at the same time, using normoxia and hypoxia in parallel. Using this innovative platform, we show that hypoxia exposure induces metastatic dissemination in a panel of 12 tumor cell lines, spanning multiple indications and that a specific drug, currently under clinical development, targeting hypoxia-induced tumor metabolism, is effective in killing tumor cells and reducing metastatic dissemination only under hypoxic conditions, thereby validating the proposed mechanism of action. In conclusion, we have developed a hypoxia-ZTX screening system that allows identification of alternate indications for approved drugs or drugs in phase II or III, expanding the possibility for on-labeled use of anti-cancer therapeutics. Specifically, we demonstrated that a novel drug candidate targeting a specific hypoxia-induced signaling pathway show high anti-tumor efficacy, reduces primary tumor burden, and inhibits metastatic dissemination. This drug would thereby be promising for expanded clinical development and on-label use. Citation Format: Gabriela Vazquez Rodriguez, Zaheer Ali, Malin Vildevall, Anna Erkstam, Andreas Goutopoulos, Anna Fahlgren, Lasse D. Jensen. Recapitulating and targeting hypoxia-induced tumor metabolism using zebrafish tumor-derived xenografts-models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2337.

Precision medicine approaches based on DNA or RNA analyses, are often not identifying actionable mutations in the patients, and have not been established for predicting presonse to commonly used drugs such as platins and taxols. In epithelial ovarian cancer (EOC), where paclitaxel and carboplatin is the most commonly used first-line treatment, however, local practice and a host of clinical studies have/are evaluating combinations with other drugs, implying that first line treatment regimens may vary in different countries and regions. As EOC patients that respond to first-line treatment have much better prognosis that those who don't, there is an urgent need for methods to predict the outcome to various available first line therapies, prior to treatment onset, so that the optimal treatment can be identified and offered to every patient. Zebrafish tumor xenograft (ZTX) models have recently been used to predict treatment outcome to first line therapy in multiple myeloma, neuroendocrine cancer, colorectal cancer and gastric cancer, but these studies have been small case studies including only a few patients. Furthermore, EOC, and the main drugs used to treat them have, however, not been studied in ZTX models in the past. Here we present results from the first 81 patients in an ongoing clinical study to delineate the sensitivity and specificity of ZTX models to predict treatment outcome to paclitaxel and carboplatin. Of these 81 patients, 21 presented with a primary tumor only, whereas 60 had metastatic disease. To date, 25 patient-derived tumor xenograft models have been developed by random selection of samples from this patient cohort, of which 12 were from paired primary and metastatic lesions from 6 patients. We show that tumors generated from metastatic omental lesions exhibited similar growth and metastatic dissemination as those generated from samples taken from ovarian lesions. Among the 25 patient models generated, 15 were analyzed for efficacy of paclitaxel and carboplatin in the ZTX models. We found that 11 of 15 responded to paclitaxel, 12 of 15 to carboplatin and 10 of 15 to both drugs. In conclusion, ZTX EOC models established from surgical samples allow prediction of treatment outcomes to 1st line treatment and thereby may aid treatment planning in the future. Citation Format: Karthik Selvaraj, Malin Vildevall, Lina Wirestam, Zaheer Ali, Anna Erkstam, Annelie Abrahamsson, Åsa Rydmark Kersley, Preben Kjölhede, Stig Linder, Charlotta Dabrosin, Anna Fahlgren, Lasse Jensen. Zebrafish tumor-derived xenograft-models for improved diagnosis and treatment planning in ovarian cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3000.

Breast cancer (BC) is the most common malignancy in women worldwide and metastasis is the principal cause of death. As BC is a highly heterogeneous disease, different drugs must be used according to each BC subtype. However, highly individual differences in treatment outcome exist even within subtypes, and the mechanisms underlying treatment response variability between BC patients is poorly understood. The use of cell lines in vitro or in vivo generally does not recapitulate the patient-specific differences in progression and treatment outcome. Analyses of patient-derived xenograft (PDX) models grown in mice solve this problem, but these techniques are resource-intensive and optimized for studying the effects on primary tumor growth rather than metastatic dissemination. Hence, there is a great and unmet need for alternative in vivo models that give accurate insights into metastatic properties of the PDX models, and which are better suited for screening libraries of drug candidates in many PDX models within a short period of time. Here we report the development of a zebrafish tumor xenograft (ZTX) platform for screening anti-tumor and anti-metastatic drug efficacy in a panel of 20 BC PDX models and comparing these to treatment outcome in mouse-PDX models and disease-stage of the patients. ZTX models have recently gained enormous popularity as an exciting new tool in the preclinical oncology research toolbox but have not yet been exploited as a platform for analyzing PDX models in general including BC PDX models. We show that of 20 PDX models tested, 19 models implanted effectively in zebrafish larvae (95% implantation success) exhibiting an average growth rate of 49% during the three-day assay period. Increased dissemination of implanted tumor cells in the zebrafish larvae correlated with clinical data on advancing tumor stage from stage 1 to stage 3 disease. Interestingly, response to docetaxel and trastuzumab in the ZTX platform was identical in 14 of 18 cases to that in the mouse PDX models showing prediction of positive treatment outcome in 11 of 14 sensitive models and prediction of resistance in 3 of 4 resistant models. In conclusion, ZTX models established from BC PDX material closely recapitulate the dissemination phenotypes of the patients from where the PDX models is generated, and treatment outcomes in the corresponding mouse-PDX models. The ZTX platform provides new opportunities for fast and accurate drug or PDX screens of anti-tumor and anti-metastatic efficacy. Citation Format: Gabriela Vazquez Rodriguez, Zaheer Ali, Anna Erkstam, Julia Schueler, Anna Fahlgren, Lasse D. Jensen. Zebrafish tumor-derived xenografts established from breast cancer pdx models predict treatment outcome and dissemination risk with superior sensitivity and specificity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2995.

Background Diagnosis of childhood TB (tuberculosis) is challenging because its symptoms resemble other diseases, very few (less than five) mycobacteria are capable of causing the disease and children do not or rarely expectorate. These peculiar attributes make childhood TB different from adult TB but it is still not being dealt differently from adult TB .Despite evidences from national, international data and WHO recommendation for use of Gene expert/TB/RIF assay, decision to start the treatment is based mostly on Chest X ray, tuberculin skin test, history of contact and clinical sign and symptoms .Therefore, we planned this study to find best available choices of diagnostic tests for early case detection of childhood TB particularly MDR TB Methods: This comparative analytical study of 15 months was done at PHRC, SRCCH, NICH and Provincial TB Lab Ojha Institute of chest diseases Karachi. Our study population comprised of 143 probable cases of pulmonary TB below the age of 15 years. After taking written consent from parent/guardian, a Performa was filled with contact no, address, clinical history, scoring chart and diagnostic tests suggested by attending clinician. ZN staining for smear microscopy GeneXpert Mycobacterium tuberculosis Rifampicin (Xpert MTB/RIF) assay, Culture on Lowenstein–Jensen (L.J) media and Mycobacterium Growth Indicator Tube (MGIT) was done for every sample according to standard operating procedures of WHO and results were entered and analyzed on SPSS statistical package for social sciences. Results Out of 143 samples 7 (5%) were positive for MTB via Xpert MTB/RIF assay while 3(2.09) were positive through AFB microscopy, LJ culture and MGIT. When compared with gold standard blood culture sensitivity and negative predictive value of Xpert MTB/RIF were 100% and 97.14% while specificity and positive predictive value were 97.14% and 43% respectively. Conclusion Xpert MTB/RIF is a rapid test that can aid in timely diagnosis of peds TB, facilitating the timely treatment. However, specificity and PPV need to be taken into account. Key words: AFB microscopy, LJ and MGIT, Xpert MTB/RIF, Peds TB.

Aberrant ocular angiogenesis can underpin vision loss in leading causes of blindness, including neovascular age-related macular degeneration and proliferative diabetic retinopathy. Current pharmacological interventions require repeated invasive administrations, may lack efficacy and are associated with poor patient compliance and tachyphylaxis. Vitamin D has de novo anti-angiogenic properties. Here, our aim was to validate the ocular anti-angiogenic activity of biologically active vitamin D, calcitriol, and selected vitamin D analogue, 22-oxacalcitriol. Calcitriol induced a significant reduction in ex vivo mouse choroidal fragment sprouting. Viability studies in a human RPE cell line suggested non-calcemic vitamin D analogues including 22-oxacalcitriol have less off-target anti-proliferative activity compared to calcitriol and other analogues. Thereafter, the anti-angiogenic activity of 22-oxacalcitriol was demonstrated in an ex vivo mouse choroidal fragment sprouting assay. In zebrafish larvae, 22-oxacalcitriol was found to be anti-angiogenic, inducing a dose-dependent reduction in choriocapillaris development. Subcutaneously administered calcitriol failed to attenuate mouse retinal vasculature development. However, calcitriol and 22-oxacalcitriol administered intraperitoneally, significantly attenuated lesion volume in the laser-induced choroidal neovascularisation mouse model. In summary, calcitriol and 22-oxacalcitriol attenuate ex vivo and in vivo choroidal vasculature angiogenesis. Therefore, vitamin D may have potential as an interventional treatment for ophthalmic neovascular indications.