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The present study aimed to use a comprehensive approach for evaluating 12 factors related to embryo quality (shape, size and transparency), donors (age, ET type, number of recovered embryos and day of uterine flushing), recipients (age), males (age and individual variations) and environment (season and year) which could affect the outcome of ET in terms of pregnancy (PR) and pregnancy losses in dromedary camels. During three breeding seasons, 116 donor females were mated repeatedly at 12- to 14-day intervals by fertile male camels (n = 33) without stimulation of the ovaries (WSPO). Superovulation (SPO ET) regimen was applied for each donor female twice or thrice per season. In the occasions of applying superovulation regimen, donor females having an ovulatory follicle were mated instead of GnRH administration and superovulation regimen was applied 4 days post-mating (MIX ET). The uteri of all donor females were flushed at Day 8 or 9 post-mating, and a total of 2,095 embryos were recovered and transferred individually to 924 recipient females. Pregnancy diagnoses were conducted at Day 10 after ET (Days 18-19 of gestation) by using progesterone assay and by transrectal ultrasonography (TRU) at Days 30 and 60 of gestation. By using logistic regression analysis, transparency of embryos and age of recipient females had significant effects on PR at Days 18-19 (p .01), 30 (p .01) and 60 (p .01; p .05, respectively) of gestation. The shape of embryos had significant effects on the PR at Days 30 (p .05) and 60 (p .01) of gestation. Type of ET and the breeding season (year) had significant (p .05) effects on the PR at Day 30, while day of flushing had the same effect on PR at Day 60. Regarding the pregnancy losses, transparency and shape of the embryo, type of ET, breeding season had significant (p .05) effect on the late embryonic mortalities (LEM) and shape and season of year had significant (p .01 and p .05, respectively) effect on LEM/early foetal mortalities (EFM). Regarding male individual factor, there was a tendency for a significant (p = .055) effect of male camels on the PR at Days 18-19 and rate of LEM. In conclusion, transferring a spherical, transparent or a large-sized embryo (750 µm) into recipient females ageing between 8 and 11 y could greatly improve the PR from Days 18 to 60 of gestation. Also, embryo recovered from donor females with Mix ET type or embryos sired by certain male camel or at Day 8 post-mating of the donor could improve the 2-month PR. In addition, transferring a transparent or spherical-shaped embryo or embryos recovered from donor females with SPO or Mix ET could reduce the pregnancy losses during the first 2 months of pregnancy.

The key aim of the study was to investigate the role of social entrepreneurship in poverty alleviation in district Mardan. The researcher studied previous investigations, associated with this study earlier while adopting the study method. To find out the specific objectives of the study, the researcher followed quantitative method, based on the past study of Chebbi (2016), and data was collected through questionnaire. The questionnaire was a developed questionnaire from the study of Ali and Ali, (2013).The questionnaire was distributed to 200 social entrepreneurs providing their services in different local and international NGOs, social welfare foundations operating in district Mardan. In response, a total of 150 questionnaires were received, the response rate was 75%. It is a good response rate. In which 68.7% were male while the percentage of female respondents were 31.3. In which the percentage of age group under 20 were 2%, from 20-30 their percentage were 64.7, while the percentage of the respondents with 31-40 age group were 16.7, and the age group from 41 to 50 their percentage were 12.7. While the age of the respondents above 50 were of 4.0%.In the total 150 of the respondents, there were 55.3% single respondents while 43.7% were married respondents. Similarly, the respondents having no education or illiterate, their percentage were 0.0, while the respondents having highest school level education, there were of 4.7%, and the respondents having highest college level education there percentage were 6.7, while the respondents having highest level of education were university graduate, their percentage were 87.7%. Likewise, the obtained data were entered and analysed by SPSS.

SummaryNon-alcoholic fatty liver disease (NAFLD) is a rapidly growing cause of morbidity with few treatment options available. Thus, accuratein vitrosystems to test new therapies are indispensable. Recently, human liver organoid (HLO) NAFLD models have emerged. However, a systematic evaluation of their translational potential is currently missing. Here, we develop a structured approach to evaluate NAFLD-HLO models, testing oleic acid (OA) and palmitic acid (PA) in comparison to TGF-β1 for disease induction. Through analysis of ∼100K single-cell transcriptomes of the HLO injury landscape, we find all three models induce inflammatory signatures. However, only TGF-β1 promotes collagen production, fibrosis, and hepatic stellate cell (HSC) expansion. In striking contrast, OA ameliorates fibrotic signatures and reduces the HSC population. Integrating data from each model with that of NAFLD patients across disease progression further demonstrates PA and TGF-β1 more robustly model inflammation and fibrosis. Our findings highlight the importance to stratify NAFLD-HLO models by clinical disease progression, provide a single-cell reference to benchmark future organoid injury models, and allow us to study evolving steatohepatitis, fibrosis, and HSC susceptibility to injury in a dynamic, multi-lineage humanin vitrosystem.

Altered enteric microorganisms in concert with host genetics shape inflammatory bowel disease (IBD) phenotypes. However, insight is limited to bacteria and fungi. We found that eukaryotic viruses and bacteriophages (collectively, the virome), enriched from non-IBD, noninflamed human colon resections, actively elicited atypical anti-inflammatory innate immune programs. Conversely, ulcerative colitis or Crohn’s disease colon resection viromes provoked inflammation, which was successfully dampened by non-IBD viromes. The IBD colon tissue virome was perturbed, including an increase in the enterovirus B species of eukaryotic picornaviruses, not previously detected in fecal virome studies. Mice humanized with non-IBD colon tissue viromes were protected from intestinal inflammation, whereas IBD virome mice exhibited exacerbated inflammation in a nucleic acid sensing–dependent fashion. Furthermore, there were detrimental consequences for IBD patient–derived intestinal epithelial cells bearing loss-of-function mutations within virus sensor MDA5 when exposed to viromes. Our results demonstrate that innate recognition of IBD or non-IBD human viromes autonomously influences intestinal homeostasis and disease phenotypes. Thus, perturbations in the intestinal virome, or an altered ability to sense the virome due to genetic variation, contribute to the induction of IBD. Harnessing the virome may offer therapeutic and biomarker potential.

Inflammatory bowel disease (IBD) is driven by host genetics and environmental factors, including commensal microorganisms. Epigenetics facilitate integration of environmental cues for transcriptional output. However, evidence of epigenetic dysregulation directly causing host-commensal dysbiosis and IBD is lacking. Speckled Protein 140 (SP140) is an immune-restricted chromatin ‘reader’ with homology to Autoimmune Regulator (AIRE). SP140 mutations associate with three immune diseases: Crohn’s disease (CD), multiple sclerosis (MS) and chronic lymphocytic leukemia (CLL), but disease-causing mechanisms remain undefined. Here we identify a critical immune-intrinsic role for SP140 in preventing expansion of inflammatory Proteobacteria, including Helicobacter in mice and Enterobacteriaceae in humans. Mice harboring altered microbiota due to hematopoietic Sp140 deficiency exhibited severe colitis which was transmissible upon co-housing and ameliorated with antibiotics. SP140 was critical for calibration of macrophage microbicidal responses required for normal host-commensal crosstalk and elimination of invasive pathogens. Mutations within this epigenetic reader may constitute a predisposing event in human diseases provoked by the microbiome, such as IBD and MS.

This research investigates the relationship between enterprise environmental factors (EEFs) and programme management (PgM) resources, and subsequently how PgM resources and sustainability integrate into social enterprise. With a resource-based view (RBV) concept as the theoretical starting point, a systematic literature review identified EEFs relating to PgM resources, and PgM resources relating to sustainability in private and public organisations. A mixed-method research approach was used that is founded on a sequential exploratory strategy. In the preliminary phase, meta qualitative analysis was conducted; in the second phase, 16 semi structured interviews were undertaken to customise and confirm the concepts by using thematic analysis within 4 selected case studies. In the final phase, the model was validated by a survey that returned (n = 302) completed questionnaires from around Pakistan, and the used method of analysis was PLS-SEM. These research findings highlight that PgM resources within social enterprises are highly influential and dependent on external and internal EEFs, and that PgM resources are critical to consider for social enterprise sustainability. In addition, this study highlights that PgM resources positively influence social, economic, and environmental sustainability in SEs. Furthermore, this study developed a validated novel theoretical framework.

SummaryAltered enteric microorganisms in concert with host genetics shape inflammatory bowel disease (IBD) phenotypes. However, insight is limited to bacteria and fungi. We found virus like particles (VLPs) enriched from normal human colon resections, containing eukaryotic viruses and bacteriophages (collectively, the virome), actively elicited atypical anti-inflammatory innate immune programs. Conversely, IBD patient VLPs provoked inflammation, which was successfully dampened by healthy VLPs. The IBD colon tissue virome was perturbed, including enriched PicornovirusEnterovirus B,not previously observed in fecal virome studies. Mice with humanized healthy colon tissue viromes had attenuated intestinal inflammation while those with IBD-derived viromes exhibited exacerbated inflammation in a nucleic acid sensing-dependent fashion. Furthermore, there were detrimental consequences for IBD-associated MDA5 loss-of-function on patient intestinal epithelial cells exposed to healthy or IBD viromes. Our results demonstrate that innate recognition of either healthy or IBD human viromes autonomously influences disease phenotypes in IBD. Harnessing the virome may offer therapeutic and biomarker potential.One Sentence SummaryHuman viromes divergently shape host immunity and disease

Chronic liver injury causes fibrosis, characterized by the formation of scar tissue resulting from excessive accumulation of extracellular matrix (ECM) proteins. Hepatic stellate cell (HSC) myofibroblasts are the primary cell type responsible for liver fibrosis, yet there are currently no therapies directed at inhibiting the activity of HSC myofibroblasts. To search for potential anti-fibrotic drugs, we performed a high-throughput compound screen in primary human HSC myofibroblasts and identified 19 small molecules that induce HSC inactivation, including the polyether ionophore nanchangmycin (NCMC). NCMC induces lipid re-accumulation while reducing collagen expression, deposition of collagen in the extracellular matrix, cell proliferation, and migration. We find that NCMC increases cytosolic Ca2+ and reduces the phosphorylated protein levels of FYN, FAK, ERK1/2, HSP27 and STAT5B. Further, depletion of each of these kinases suppress COL1A1 expression. These studies reveal a signaling network triggered by NCMC to inactivate HSC myofibroblasts and reduce expression of proteins that compose the fibrotic scar. The identification of the antifibrotic effects of NCMC and the pathways by which NCMC inhibits fibrosis provides new tools and therapeutic targets to combat the development and progression of liver fibrosis.

Chronic liver injury causes fibrosis, characterized by the formation of scar tissue resulting from excessive accumulation of extracellular matrix (ECM) proteins. Hepatic stellate cell (HSC) myofibroblasts are the primary cell type responsible for liver fibrosis, yet there are currently no therapies directed at inhibiting the activity of HSC myofibroblasts. To search for potential anti-fibrotic compounds, we performed a high-throughput compound screen in primary human HSC myofibroblasts and identified 19 small molecules that induce HSC inactivation, including the polyether ionophore nanchangmycin (NCMC). NCMC induces lipid re-accumulation while reducing collagen expression, deposition of collagen in the extracellular matrix, cell proliferation, and migration. We find that NCMC increases cytosolic Ca2+ and reduces the phosphorylated protein levels of FYN, PTK2 (FAK), MAPK1/3 (ERK2/1), HSPB1 (HSP27), and STAT5B. Further, depletion of each of these kinases suppress COL1A1 expression. These studies reveal a signaling network triggered by NCMC to inactivate HSC myofibroblasts and reduce expression of proteins that compose the fibrotic scar. Identification of the antifibrotic effects of NCMC and the elucidation of pathways by which NCMC inhibits fibrosis provide new tools and therapeutic targets that could potentially be utilized to combat the development and progression of liver fibrosis.

Social Media (SM) is considered one of the most discussed topics in today&rsquo, s business environment, mostly because of the recent developments and improvements in computer and ICT (Information and Communications Technology) technologies. However, very little is known about Social Media&rsquo, s (SM) role in creating Small and Medium-sized Enterprises&rsquo, (SMEs&rsquo, ) financial sustainability. Drawing upon the Technology Organisational and Environmental (TOE) framework, the authors constructed a comprehensive model that examined the role of different factors in the adoption of SM by SMEs in developing countries (using Pakistan as an example). Using a questionnaire survey of 383 owners/managers of SMEs in Pakistan, the research findings determined the different factors (i.e., organisational, technological, and environmental), which can impact the adoption of SM by SMEs. In line with previous research studies, the results of structural equation modelling show that technological factors such as perceived benefits of SM, compatibility of SM, cost, and trust have a substantial effect on SMEs&rsquo, SM adoption. Similarly, both organisational factors: top management support and technological competence, are strong predictors of SM adoption in SMEs. Finally, environmental factors (i.e., competitor pressure, customer pressure, and information intensity) positively impacted SM adoption by SMEs. The effect of SM adoption on SMEs&rsquo, financial sustainability was also tested and found to be positive and significant. Several theoretical and practical implications for owners/managers and other stakeholders regarding SM&rsquo, s successful implementation by SMEs are highlighted within the paper.

Background: The use of objective endpoints is critical for the generalization and clinical implications of a study. Overall survival (OS) has traditionally been used as the gold standard for demonstrating the true clinical benefit of a therapy or intervention. Use of clinically meaningful pre-specified endpoints is essential for a successful clinical trial. In this systemic review, we aimed to investigate different primary and secondary endpoints used in phase III randomized controlled trials (RCTs) for hematopoietic stem cell transplantation (HCT), and their trends over a span of 15 years. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a comprehensive literature search was conducted on three databases (PubMed, Cochrane, and Clinical trials.gov) using MeSH terms and keywords for "hematopoietic stem cell transplantation" AND "Randomized Controlled Trials as Topic" from January 2006 to May 2021. We screened 2223 articles. After excluding duplicates, reviews, and irrelevant articles, 170 articles reporting only phase III RCTs with primary and secondary endpoints on HCT were included for our systematic review. Primary and secondary endpoints data were extracted from the included studies and the frequency of various endpoints as well as their yearly frequencies were calculated. Disease-free survival (DFS) was used to represent similar outcomes including event-free survival (EFS), progression-free survival (PFS), leukemia-free survival (LFS), and relapse-free survival (RFS). Results: Our study included 154 phase III RCTs on HCT. DFS was the primary endpoint in 40 (26%) studies, while OS and graft versus host disease (GvHD) were reported as primary endpoints in 40 (26%) and 13 (8%) studies, respectively. Infections, response rate, relapse rate (RR), toxicity/adverse events, quality of life (QoL), non-relapse mortality (NRM)/transplant-related mortality (TRM), GvHD-free survival, and hematological improvement (HI) were used as primary endpoints in 13 (8%), 13 (8%), 12 (8%), 8 (5%), 7 (4.5%), 7 (4.5%), 6 (4%), and 5 (3%) studies respectively. Other infrequently reported primary endpoints are listed in Table 1. Secondary endpoints followed a similar pattern as detailed in Table 2. OS (n=26, 40%), toxicity/adverse events (n=33, 21%), and TRM/NRM (n=33, 21%) were commonly reported secondary endpoints. DFS, GvHD, RR, QoL, infections, response rate, disease progression, and hematopoietic engraftment were used as secondary endpoints in 29 (19%), 28 (18%), 21 (14%), 17 (11%), 17 (11%), 13 (8%), 8 (5%), and 8 (5%) studies, respectively. After 2013, decrease in the use of DFS (27% to 25%) and OS (31% to 23%) as a primary endpoint was noted. For secondary endpoints, a higher trend in the use of OS (18% to 30%) and NRM/TRM (18% to 23%) was observed after 2013. (Table 2) Conclusion: Disease-free survival was the most common primary endpoint and overall survival was the most common secondary endpoint in phase III randomized controlled trials for hematopoietic stem cell transplantation over the last 15 years. The use of QoL as an endpoint remained low in RCTs. Newly introduced composite endpoint of GvHD-free relapse-free survival (GRFS) may be considered as a primary endpoint in future prospective studies. Figure 1 Figure 1. Disclosures Abhyankar: Incyte/Therakos: Consultancy, Research Funding, Speakers Bureau. McGuirk: Pluristem Therapeutics: Research Funding; Bellicum Pharmaceuticals: Research Funding; Gamida Cell: Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Fresenius Biotech: Research Funding; EcoR1 Capital: Consultancy; Novartis: Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Astelllas Pharma: Research Funding.

Background: The use of objective endpoints is critical for the generalization and clinical implications of a study. Overall survival (OS) has traditionally been used as the gold standard for demonstrating the true clinical benefit of therapy or intervention. We systematically evaluated the proportion of different primary and secondary endpoints used in phase III randomized controlled trials (RCTs) for acute myeloid leukemia (AML), and their trends over time. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a comprehensive literature search was conducted on three databases (PubMed, Cochrane, and Clinical trials.gov) using MeSH terms and keywords for "Leukemia, Myeloid, Acute" AND "Randomized Controlled Trials as Topic" from January 2006 to March 2021. We screened 3290 articles. After excluding duplicates, reviews, and irrelevant articles, 241 articles reporting only phase III RCTs with primary and secondary endpoints on AML or its subtypes were included for our systematic review. Primary and secondary endpoints data were extracted from the included studies, and the frequency of various endpoints as well as their yearly frequencies were calculated. Disease-free survival (DFS) was used to represent similar outcomes including event-free survival (EFS), progression-free survival (PFS), leukemia-free survival (LFS), and relapse-free survival (RFS). Results: Our study included 241 phase III RCTs on AML. OS was the primary endpoint in 114 (47%) studies, while DFS and complete remission (CR) were reported as primary endpoints in 67 (28%) and 41 (17%) studies, respectively. Safety/adverse events, relapse rate (RR), graft versus host disease (GvHD) free survival, hematological improvement (HI), minimal residual disease (MRD), and non-relapse mortality (NRM) were used as primary endpoints in 10 (4%), 8 (3%), 5 (2%), 4 (2%), 3 (1%), and 2 (1%) studies respectively. Incidence of hospitalization, fungal disease, lung infiltrates, chronic GvHD, and allogeneic stem cell transplant each were used as primary endpoints in 1 (0.4%) study. (Table 1) Secondary endpoints followed a similar pattern as detailed in Table 2. OS (n=74, 31%), DFS (n=77, 32%) and CR (n=73, 30%) were commonly reported secondary endpoints. Safety/adverse effects, RR, mortality, quality of life (QoL), HI, MRD, incidence/length of hospitalization, and acute/chronic GvHD were used as secondary endpoints in 35 (14.5%), 15 (6%), 13 (5%), 9 (4%), 9 (4%), 7 (3%), 7 (3%), 5 (2%), and 4 (2%) studies, respectively. After 2013, increase in the use of OS (31% to 52%) and CR (15% to 17%) as a primary endpoint was noted, while the use of DFS as a primary endpoint decreased from 52% to 21%. (Table 1) For secondary endpoints, a higher trend in the use of DFS (19% to 35%) and OS (31% to 45%) and a lower trend in the use of CR (35% to 29%) was observed after 2013. (Table 2) Conclusion: Overall survival and disease-free survival were the most used primary and secondary endpoints in phase III randomized controlled trials for AML. There has been an increase in the use of clinically meaningful and objective endpoint of OS over the past 15 years in AML phase III RCTs. Figure 1 Figure 1. Disclosures Yacoub: Cara: Current equity holder in publicly-traded company; Dynavex: Current equity holder in publicly-traded company; Agios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ACCELERON PHARMA: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Ardelyx: Current equity holder in publicly-traded company; Seattle Genetics: Honoraria, Speakers Bureau; Hylapharm: Current equity holder in publicly-traded company. Lin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. McGuirk: Pluristem Therapeutics: Research Funding; Novartis: Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Gamida Cell: Research Funding; EcoR1 Capital: Consultancy; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Fresenius Biotech: Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Bellicum Pharmaceuticals: Research Funding; Astelllas Pharma: Research Funding.

AIM To understand the experience of maternal depression, the factors implicated in accessing health, and the acceptability of the psychosocial intervention. METHODS The participants were recruited from the paediatrics outpatient department of Civil Hospital Karachi, Pakistan. The study started in December 2009 and completed in December 2010. Women with maternal depression, aged 18-44 years with children aged 0-30 mo who had received nutritional supplements, and participated in the intervention programme [called Learning through Play (LTP) plus] were included in the study. Qualitative interviews were conducted with 8 participants before the intervention and 7 participants after the intervention. A semi structured topic guide was used to conduct the interviews. RESULTS Framework analysis procedures were used to analyse the qualitative data. Four themes emerged: (1) the women’s contextual environment: Interpersonal conflicts, lack of social support and financial issues being the major barriers in assessing healthcare; (2) women’s isolation and powerlessness within the environment: Sense of loneliness was identified as a restricting factor to access healthcare; (3) the impact of the intervention (LTP-Plus): Women felt “listened to” and seemed empowered; and (4) empowered transformed women within the same contextual environment: The facilitator provided a “gardening role” in nurturing the women resulting in a positive transformation within the same environment. The women’s homes seemed to be more happy homes and there was a positive change in their behaviour towards their children. CONCLUSION Findings informed the further development and testing of culturally-appropriate psychosocial intervention (LTP+) for addressing maternal depression.

NeuroLNC, a previously unknown long ncRNA, regulates neuronal activity by interacting with the neurodegeneration protein TDP-43., The cellular and the molecular mechanisms by which long noncoding RNAs (lncRNAs) may regulate presynaptic function and neuronal activity are largely unexplored. Here, we established an integrated screening strategy to discover lncRNAs implicated in neurotransmitter and synaptic vesicle release. With this approach, we identified neuroLNC, a neuron-specific nuclear lncRNA conserved from rodents to humans. NeuroLNC is tuned by synaptic activity and influences several other essential aspects of neuronal development including calcium influx, neuritogenesis, and neuronal migration in vivo. We defined the molecular interactors of neuroLNC in detail using chromatin isolation by RNA purification, RNA interactome analysis, and protein mass spectrometry. We found that the effects of neuroLNC on synaptic vesicle release require interaction with the RNA-binding protein TDP-43 (TAR DNA binding protein-43) and the selective stabilization of mRNAs encoding for presynaptic proteins. These results provide the first proof of an lncRNA that orchestrates neuronal excitability by influencing presynaptic function.

Evidence demonstrates the detrimental impact of depression in patients with congestive heart failure (CHF), however, large-scale prospective data from Low and Middle Income Countries (LMICs) is limited. We assessed the prevalence of depression in a large sample with CHF from Karachi, Pakistan, and the impact of depression on all-cause mortality, disability and health-related quality of life (QoL).1009 patients diagnosed with CHF were recruited from public hospitals in Karachi, Pakistan. Patients were screened for depression at baseline using the Beck Depression Inventory (BDI) and the diagnosis was confirmed using the Clinical Interview Schedule-Revised (CIS-R). Health-related QoL and disability were measured using the EuroQol (EQ-5D) and Brief Disability Questionnaire respectively at baseline and after a 6-month follow-up.A total of 670 (66%) patients were depressed at baseline and 821 participants completed 6-month follow up assessments (retention rate: 81%). At baseline, lower income (p 0.001) and lower education level (p = 0.03) were associated with higher BDI scores. Higher BDI scores were associated with a history of depression (p 0.001), higher NYHA class (p 0.001), diabetes (p 0.001), COPD (p = 0.007), renal disease (p 0.001) and stroke (p = 0.02). 145 participants were deceased at 6-months. Regression analysis showed that at follow up, higher BDI scores in depressed participants were associated with higher all-cause mortality (OR 1.23 (95% CI: 1.11-1.36); p 0.001).The rate of depression was high among Pakistani patients with CHF. Severity of depression correlated with increased mortality. Further research on controlled intervention trials in this population is warranted.

The homeostasis of the proteome depends on the tight regulation of the mRNA and protein abundances, of the translation rates, and of the protein lifetimes. Results from several studies on prokaryotes or eukaryotic cell cultures have suggested that protein homeostasis is connected to, and perhaps regulated by, the protein and the codon sequences. However, this has been little investigated for mammals in vivo. Moreover, the link between the coding sequences and one critical parameter, the protein lifetime, has remained largely unexplored, both in vivo and in vitro. We tested this in the mouse brain, and found that the percentages of amino acids and codons in the sequences could predict all of the homeostasis parameters with a precision approaching experimental measurements. A key predictive element was the wobble nucleotide. G-/C-ending codons correlated with higher protein lifetimes, protein abundances, mRNA abundances and translation rates than A-/U-ending codons. Modifying the proportions of G-/C-ending codons could tune these parameters in cell cultures, in a proof-of-principle experiment. We suggest that the coding sequences are strongly linked to protein homeostasis in vivo, albeit it still remains to be determined whether this relation is causal in nature.

Oasis2-Suppl-Material.docx: This file contains supplementary material and figures as well. (DOCX 125 kb)

Most internally displaced persons (IDPs) live in low-income countries experiencing a war; their psychosocial health has not been well addressed. Objectives: To find out the prevalence of anxiety and depression in internally displaced persons (IDPs). Design: A randomized cluster sampling, case-controlled study. Period: 10th April 2009 to 10th July 2009. Setting: This study was conducted at Kacha Ghari camp and Sheikh Yaseen camp for IDPs. Patients and Method: A total of 220 cases (those whom were exposed to traumatic experiences) were selected through cluster random sampling. 220-matched controls (those whom were not exposed to traumatic experiences) were selected same day using the same sampling method. Both sexes were included. Socio-demographic information was obtained from IDP- information form. Anxiety and depression was assessed using Hopkins symptoms checklist - 25 (HSCL-25). SPSS version -17 was used for statistical analysis. Chi square test was applied for group comparison to calculate statistical significance. Results: More than half of the participants (60 %) in this study were in age group between 18 to 38 years. 55 % of the population were females. Majority of participant were married (86% - 90%) and were uneducated (74% - 90%) belongs to lower socio-economical class. The total Scores and the Depression Scores on Hopkins symptoms checklist - 25 (HSCL-25), were significant high in case group than in control group with the P values of 0.04 and 0.05 respectively. Discussion: Trauma and torture leaves a permanent scar on the survivors. It has physical, psychological and social squeals. Hopkins Symptoms Checklist-25 is intended to provide primary care physicians, mental health practitioners and other health care providers with an instrument for detecting anxiety and depression in torture and trauma victims. Conclusions: Besides being displaced from their residence exposure to trauma come out to be the important causative factor in creating psychological disturbance among internally displaced persons.

We present the Small RNA Expression Atlas (SEA), a web application that allows for the interactive querying, visualization, and analysis of known and novel small RNAs across ten organisms. It contains sRNA and pathogen expression information for over 4,200 published samples with standardized search terms and ontologies. In addition, SEA allows for the interactive visualization and re-analysis of 879 differential expression and 514 classification comparisons. SEA’s user model enables sRNA researchers to compare and re-analyze user-specific and published datasets, highlighting common and distinct sRNA expression patterns.We provide evidence for SEA’s fidelity by (i) generating a set of 591 tissue specific miRNAs across 30 tissues, (ii) finding known and novel bacterial and viral infections across diseases, and (iii) determining a Parkinson’s disease-specific blood biomarker signature using novel data.We believe that SEA’s simple semantic search interface, the flexible interactive reports, and the user model with rich analysis capabilities will enable researchers to better understand the potential function and diagnostic value of sRNAs or pathogens across tissues, diseases, and organisms.Availability and ImplementationSEA is implemented in Java, J2EE, spring, Django, html5, css3, JavaScript, Bootstrap, Vue.js, D3, mongodb and neo4j. It is freely available athttp://sea.ims.bio/.

Oasis 2 is a new main release of the Oasis web application for the detection, differential expression, and classification of small RNAs in deep sequencing data. Compared to its predecessor Oasis, Oasis 2 features a novel and speed-optimized sRNA detection module that supports the identification of small RNAs in any organism with higher accuracy. Next to the improved detection of small RNAs in a target organism, the software now also recognizes potential cross-species miRNAs and viral and bacterial sRNAs in infected samples. In addition, novel miRNAs can now be queried and visualized interactively, providing essential information for over 700 high-quality miRNA predictions across 14 organisms. Robust biomarker signatures can now be obtained using the novel enhanced classification module. Oasis 2 enables biologists and medical researchers to rapidly analyze and query small RNA deep sequencing data with improved precision, recall, and speed, in an interactive and user-friendly environment.Availability and Implementation: Oasis 2 is implemented in Java, J2EE, mysql, Python, R, PHP and JavaScript. It is freely available at http://oasis.dzne.de

Objective: To assess the risk factors for breast cancer in patients attending oncology OPD of civil hospital Karachi, Pakistan. Introduction: Breast cancer is the single largest cause of death among women1,2. The probability of American woman developing breast cancer in their life is 7 in 11. Studies from subcontinent show that the incidence of breast cancer is increasing, with an estimated 80,000 new cases diagnosed annually. Breast cancer is the second most common type of cancer after lung cancer in Pakistan and ranked first in women. Only 10% women are diagnosed, out of them, 75% women do not get treatment and die within 5 years6. Data from Pakistan about the risk factors or association is not only scanty but also does not comment on the use of fatty diet in breast cancer patients. Method: A cross-sectional descriptive study conducted at Oncology OPD of civil hospital Karachi (CHK) from October 2009 -April 2011. One Hundred and Fifty consecutive patients having histopathalogical diagnosis of breast cancer were assessed for different risk factors that included marital status, parity, age, menopausal status, family history of breast cancer, prolong use of oral contraceptives, breast feeding, , early menarche, trauma to the breast and fatty diet. Result: Mean age of patients was 48 years. Three fourth (73%) of these female were above the age of 40 years. Consumption of fatty diet was found in 62.67% while positive family history of breast cancer was present in 34% of the cases. Early menarche and being nulliparous were not as strong risk factors as in previous studies. Conclusions: Our study has highlighted the need of further exploration in this area that would not only help this population but also enhance our understanding of different risk factors. This will have important implications for the overall management of breast cancer.

Objective To examine the psychosocial correlates and association of psychological distress and quality of life (QOL) in patients with medically unexplained symptoms (MUS) compared to those with medically explained symptoms (MES) in a primary care setting in Karachi, Pakistan. Methods A cross-sectional study of 472 patients attending GP clinics between March and August 2009 in Karachi. Participants completed questionnaires to assess demographic details, somatic symptoms, anxiety, depression, and QOL. The patients' GP recorded whether the presenting complaint was medically unexplained or medically explained. Results MUS subjects in our study were more educated, had better social support and fewer financial problems, were less depressed and had a better QOL than subjects who had medically explained symptoms (non-MUS). Both groups (MUS and non-MUS) were comparable in terms of anxiety and number of somatic symptoms, but non-MUS subjects were more depressed than the MUS group. In a regression analysis, the number of somatic symptoms and lower levels of anxiety predicted poorer QOL in this sample. Whether these symptoms were medically explained (or not) did not seem to contribute significantly to the QOL. Conclusion Our findings confirm that even in the developing world, patients with MUS are common among primary care attendees. However, patients with MUS in urban Karachi, Pakistan may differ from Western MUS subjects in the role of stress, support, and anxiety in their presentation, and may be reflective of a conceptually different group of difficulties.

Background:Research in the West shows that group psychological intervention together with an antidepressant treatment leads to more effective treatment of a depressive disorder. There are no treatment trials from low income countries comparing the efficacy of antidepressant treatment with a group psychological intervention.Aim:To conduct a feasibility trial to compare the efficacy of an antidepressant to a group psychosocial intervention, for low income women attending primary health care in Karachi, Pakistan.Method:This was a preliminary RCT in an urban primary health care clinic in Karachi, Pakistan. Consecutive eligible women scoring >12 on the CIS-R and >18 on Hamilton Depression Rating Scale (HDRS) (n= 66) were randomly assigned to antidepressants or a psychosocial treatment in group settings. The primary outcome measure was HDRS score; secondary outcome measures were disability and quality of life.Results:More than half of the patients in both groups improved (50% reduction in HDRS scores); at end of therapy at 3 months 19 (59.4%) vs 18 (56.2%), and at 6-month follow-up 21(67.7%) vs 20(62.5%) for antidepressants and psychosocial intervention respectively. Although HDRS, BDQ and EQ5-D scores all improved considerably in both groups from start to end of treatment, and these improvements were largely maintained after a further 3 months, the differences between the two treatments were not statistically significant.Conclusion:Psychosocial intervention was as effective as antidepressants in reducing depression and in improving quality of life and disability at the end of therapy. However, these findings need further exploration through a larger trial.

Recent evidence suggests that the formation and maintenance of memory requires epigenetic changes. In an effort to understand the spatio-temporal extent of learning and memory-related epigenetic changes we have charted genome-wide histone and DNA methylation profiles, in two different brain regions, two cell types, and three time-points, before and after learning. In this data descriptor we provide detailed information on data generation, give insights into the rationale of experiments, highlight necessary steps to assess data quality, offer guidelines for future use of the data and supply ready-to-use code to replicate the analysis results. The data provides a blueprint of the gene regulatory network underlying short- and long-term memory formation and maintenance. This ‘healthy’ gene regulatory network of learning can now be compared to changes in neurological or psychiatric diseases, providing mechanistic insights into brain disorders and highlighting potential therapeutic avenues. Machine-accessible metadata file describing the reported data (ISA-Tab format)

Objectives: To determine the different levels of drug non-adherence in patients suffering from Depression. Design: A casecontrolled study. Place and Duration of Study: Hayatabad Medical Complex Peshawar, From February 2008 to August 2008. Patients and Method: 50-Cases were selected from the out patient department with the DSM-IV diagnosis of major depressive disorder, 50- non psychotic patients were selected as controls. Both sexes were included. The basic socio-demographic characteristics and the clinical profile of all the patients were collected. The level of drug non-adherence was recorded at week 4, week 8 and week 12. SPSS version 15 was used for statistical analysis. The applied method for group comparison was the Chi-square test. Results: The age in mean was 33.78 ± 11.30 for the sample and 30.65 ± 9.40 for control group. 38% of these patients were males and 62% females. 58% were married and uneducated from lowersocio-economical class. 70% of the study group and 59% of control group received treatment. The rates of non adherence were statistically not significant at week 4. However, at week 8 and week 12 the rates of non adherence were statistically significant with the p values of less than (0.001) respectively. Discussion: Rates of non-adherence with psychotropic / antidepressants are difficult to summarize because they varywith setting, diagnosis, severity of illness and type of adherence difficulties. Drug non-adherence is a serious clinical problem and it has direct effects on illness management and prognosis. Conclusions: The available evidence suggests that the outcome for patients who vary medication doses without consulting a professional is poor.

The ability to form memories is a prerequisite for an organism's behavioral adaptation to environmental changes. At the molecular level, the acquisition and maintenance of memory requires changes in chromatin modifications. In an effort to unravel the epigenetic network underlying both short- and long-term memory, we examined chromatin modification changes in two distinct mouse brain regions, two cell types and three time points before and after contextual learning. We found that histone modifications predominantly changed during memory acquisition and correlated surprisingly little with changes in gene expression. Although long-lasting changes were almost exclusive to neurons, learning-related histone modification and DNA methylation changes also occurred in non-neuronal cell types, suggesting a functional role for non-neuronal cells in epigenetic learning. Finally, our data provide evidence for a molecular framework of memory acquisition and maintenance, wherein DNA methylation could alter the expression and splicing of genes involved in functional plasticity and synaptic wiring.

Objectives: There is some evidence that anti-inflammatory treatment may have beneficial effects in schizophrenia and major depression. Statins are cholesterol-lowering agents but have been found to be anti-inflammatory and also decrease C-reactive protein (CRP). Ondansetron is a serotonin (5-HT3) receptor antagonist widely used to prevent nausea and vomiting in patients receiving chemotherapy for cancer. Small studies have suggested that adjunctive ondansetron is efficacious against schizophrenia symptoms. We carried out a feasibility study in schizophrenia patients (within 5 years of first diagnosis) to explore the adjunctive use of simvastatin and ondansetron on positive, negative and general psychopathology. Methods: This was a 12-week rater-blind placebo-controlled study. A total of 36 patients with DSM-IV diagnosis of schizophrenia were recruited, 12 in each arm. Patients were assessed at baseline and at 12 weeks using Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression (CGI) scale, Global Assessment of Functioning (GAF) and Abnormal Involuntary Movement Scale (AIMS). Results: Both simvastatin and ondansetron provide some evidence of a reduction in symptoms compared with treatment as usual (TAU) on PANSS total score, although this was not statistically significant. In the secondary analyses, no significant differences were seen on CGI, GAF and AIMS. Conclusions: Anti-inflammatory treatments have been shown to have some beneficial effects in schizophrenia. Both simvastatin and ondansetron provide some evidence of a reduction in symptoms compared with TAU. This study has led to a larger Stanley Medical Research Institute (SMRI)-funded, double-blind, randomized control trial.

Effective teaching is not simply the transmission ofknowledge but it is the way through which learningoccurs. Learning does not occur in a vacuum. Learnersexamine the facts to be learned against their schemabased on past experiences.