Trace element studies on Karachi populations Part V: Blood lead levels in normal healthy adults and grammar school children

Blood lead levels of healthy Karachi population were estimated. Mean levels for males, females, soldiers and school children were 34.4, 31.8, 29.9 and 38.2 micrograms/dl respectively. About 93% cases of either sex had elevated lead levels, of whom 30% males and 10% females had levels above the safety limits (40 micrograms/dl). Soldiers living in relatively pollution free area though had levels lower than the rest of the population but 91% had levels over 25 micrograms/dl and only two had acceptable levels. Ninety-two percent children showed levels above 25 micrograms/dl with a large number having levels over 40 micrograms/dl. A very small percentage had normal levels. Pollution by traffic exhaust was assumed to be the principal cause for these high levels

Q wave and non-Q wave myocardial infarction: a multivariate analysis of survival experience and clinical outcome after first diagnosis at a tertiary care hospital

Introduction: Myocardial infarction (MI) is a well-recognized clinical entity with a worldwide distribution. In the United States alone, 1.5 million cases of MI occur per year. This study compares the in-hospital mortality, 1 year mortality and time to death following a first Q-wave or non Q-wave myocardial infarction (MI).Methods: One thousand five hundred and ninety-six patients were admitted at the Aga Khan University Hospital with a diagnosis of MI over a period of four years of whom 420 patients met our inclusion criteria. Data was collected from the patients\u27 medical records and on telephone using a pretested questionnaire. Logistic regression and Cox proportional hazard models were used to analyze the data.Results: The mean age +/- sd of the patients was 59 +/- 10 years. Of the total patients, 151(36%) and 269(64%) suffered non-Q wave and Q-wave MI respectively. A higher in hospital mortality was observed in patients with Q-wave MI (n = 64, 23.8%) than those with non-Q wave MI [n = 16 (10.6%); adjusted OR = 2.76, 95% CI: 1.5-5.01]. Similarly, patients having Q-wave MI experienced increased 1 year mortality (n = 77, 28.6%) compared to patients suffering non-Q wave MI [n = 26 (17.2%); adjusted OR = 2.04, 95% CI: 1.21-3.43].CONCLUSION: Patients with Q-wave MI had a worse prognosis compared with patients with non-Q-wave MI and therefore warrant a closer follow up. Further prospective studies are needed to evaluate the efficacy of early aggressive interventions in modifying the natural history of this disease

Young people today: news media, policy and youth justice

The new sociology of childhood sees children as competent social agents with important contributions to make. And yet the phase of childhood is fraught with tensions and contradictions. Public policies are required, not only to protect children, but also to control them and regulate their behaviour. For children and young people in the UK, youth justice has become increasingly punitive. At the same time, social policies have focused more on children's inclusion and participation. In this interplay of conflict and contradictions, the role the media play is critical in contributing to the moral panic about childhood and youth. In this article, we consider media representations of “antisocial” children and young people and how this belies a moral response to the nature of contemporary childhood. We conclude by considering how a rights-based approach might help redress the moralised politics of childhood representations in the media

Patient and public involvement in medical performance processes: A systematic review

BACKGROUND: Patient and public involvement (PPI) continues to develop as a central policy agenda in health care. The patient voice is seen as relevant, informative and can drive service improvement. However, critical exploration of PPI's role within monitoring and informing medical performance processes remains limited. OBJECTIVE: To explore and evaluate the contribution of PPI in medical performance processes to understand its extent, purpose and process. SEARCH STRATEGY: The electronic databases PubMed, PsycINFO and Google Scholar were systematically searched for studies published between 2004 and 2018. INCLUSION CRITERIA: Studies involving doctors and patients and all forms of patient input (eg, patient feedback) associated with medical performance were included. DATA EXTRACTION AND SYNTHESIS: Using an inductive approach to analysis and synthesis, a coding framework was developed which was structured around three key themes: issues that shape PPI in medical performance processes; mechanisms for PPI; and the potential impacts of PPI on medical performance processes. MAIN RESULTS: From 4772 studies, 48 articles (from 10 countries) met the inclusion criteria. Findings suggest that the extent of PPI in medical performance processes globally is highly variable and is primarily achieved through providing patient feedback or complaints. The emerging evidence suggests that PPI can encourage improvements in the quality of patient care, enable professional development and promote professionalism. DISCUSSION AND CONCLUSIONS: Developing more innovative methods of PPI beyond patient feedback and complaints may help revolutionize the practice of PPI into a collaborative partnership, facilitating the development of proactive relationships between the medical profession, patients and the public

Patient and public involvement in medical performance processes: A systematic review

BACKGROUND: Patient and public involvement (PPI) continues to develop as a central policy agenda in health care. The patient voice is seen as relevant, informative and can drive service improvement. However, critical exploration of PPI's role within monitoring and informing medical performance processes remains limited. OBJECTIVE: To explore and evaluate the contribution of PPI in medical performance processes to understand its extent, purpose and process. SEARCH STRATEGY: The electronic databases PubMed, PsycINFO and Google Scholar were systematically searched for studies published between 2004 and 2018. INCLUSION CRITERIA: Studies involving doctors and patients and all forms of patient input (eg, patient feedback) associated with medical performance were included. DATA EXTRACTION AND SYNTHESIS: Using an inductive approach to analysis and synthesis, a coding framework was developed which was structured around three key themes: issues that shape PPI in medical performance processes; mechanisms for PPI; and the potential impacts of PPI on medical performance processes. MAIN RESULTS: From 4772 studies, 48 articles (from 10 countries) met the inclusion criteria. Findings suggest that the extent of PPI in medical performance processes globally is highly variable and is primarily achieved through providing patient feedback or complaints. The emerging evidence suggests that PPI can encourage improvements in the quality of patient care, enable professional development and promote professionalism. DISCUSSION AND CONCLUSIONS: Developing more innovative methods of PPI beyond patient feedback and complaints may help revolutionize the practice of PPI into a collaborative partnership, facilitating the development of proactive relationships between the medical profession, patients and the public

Neratinib plus trastuzumab is superior to pertuzumab plus trastuzumab in HER2-positive breast cancer xenograft models

Lapatinib (L) plus trastuzumab (T), with endocrine therapy for estrogen receptor (ER)+ tumors, but without chemotherapy, yielded meaningful response in HER2+ breast cancer (BC) neoadjuvant trials. The irreversible/pan-HER inhibitor neratinib (N) has proven more potent than L. However, the efficacy of N+T in comparison to pertuzumab (P) + T or L + T (without chemotherapy) remains less studied. To address this, mice bearing HER2+ BT474-AZ (ER+) cell and BCM-3963 patient-derived BC xenografts were randomized to vehicle, N, T, P, N+T, or P+T, with simultaneous estrogen deprivation for BT474-AZ. Time to tumor regression/progression and incidence/time to complete response (CR) were determined. Changes in key HER pathway and proliferative markers were assessed by immunohistochemistry and western blot of short-term-treated tumors. In the BT474-AZ model, while all N, P, T, N + T, and P + T treated tumors regressed, N + T-treated tumors regressed faster than P, T, and P + T. Further, N + T was superior to N and T alone in accelerating CR. In the BCM-3963 model, which was refractory to T, P, and P + T, while N and N + T yielded 100% CR, N + T accelerated the CR compared to N. Ki67, phosphorylated (p) AKT, pS6, and pERK levels were largely inhibited by N and N + T, but not by T, P, or P + T. Phosphorylated HER receptor levels were also markedly inhibited by N and N + T, but not by P + T or L + T. Our findings establish the efficacy of combining N with T and support clinical testing to investigate the efficacy of N + T with or without chemotherapy in the neoadjuvant setting for HER2+ BC

De novo deletions and duplications of 17q25.3 cause susceptibility to cardiovascular malformations

BACKGROUND: Genomic disorders resulting from deletion or duplication of genomic segments are known to be an important cause of cardiovascular malformations (CVMs). In our previous study, we identified a unique individual with a de novo 17q25.3 deletion from a study of 714 individuals with CVM. METHODS: To understand the contribution of this locus to cardiac malformations, we reviewed the data on 60,000 samples submitted for array comparative genomic hybridization (CGH) studies to Medical Genetics Laboratories at Baylor College of Medicine, and ascertained seven individuals with segmental aneusomy of 17q25. We validated our findings by studying another individual with a de novo submicroscopic deletion of this region from Cytogenetics Laboratory at Cincinnati Children's Hospital. Using bioinformatic analyses including protein-protein interaction network, human tissue expression patterns, haploinsufficiency scores, and other annotation systems, including a training set of 251 genes known to be linked to human cardiac disease, we constructed a pathogenicity score for cardiac phenotype for each of the 57 genes within the terminal 2.0 Mb of 17q25.3. RESULTS: We found relatively high penetrance of cardiovascular defects (~60 %) with five deletions and three duplications, observed in eight unrelated individuals. Distinct cardiac phenotypes were present in four of these subjects with non-recurrent de novo deletions (range 0.08 Mb-1.4 Mb) in the subtelomeric region of 17q25.3. These included coarctation of the aorta (CoA), total anomalous pulmonary venous return (TAPVR), ventricular septal defect (VSD) and atrial septal defect (ASD). Amongst the three individuals with variable size duplications of this region, one had patent ductus arteriosus (PDA) at 8 months of age. CONCLUSION: The distinct cardiac lesions observed in the affected patients and the bioinformatics analyses suggest that multiple genes may be plausible drivers of the cardiac phenotype within this gene-rich critical interval of 17q25.3

Targeting tumour re-wiring by triple blockade of mTORC1, epidermal growth factor, and oestrogen receptor signalling pathways in endocrine-resistant breast cancer

Background Endocrine therapies are the mainstay of treatment for oestrogen receptor (ER)-positive (ER+) breast cancer (BC). However, resistance remains problematic largely due to enhanced cross-talk between ER and growth factor pathways, circumventing the need for steroid hormones. Previously, we reported the anti-proliferative effect of everolimus (RAD001-mTORC1 inhibitor) with endocrine therapy in resistance models; however, potential routes of escape from treatment via ERBB2/3 signalling were observed. We hypothesised that combined targeting of three cellular nodes (ER, ERBB, and mTORC1) may provide enhanced long-term clinical utility. Methods A panel of ER+ BC cell lines adapted to long-term oestrogen deprivation (LTED) and expressing ESR1wt or ESR1Y537S, modelling acquired resistance to an aromatase-inhibitor (AI), were treated in vitro with a combination of RAD001 and neratinib (pan-ERBB inhibitor) in the presence or absence of oestradiol (E2), tamoxifen (4-OHT), or fulvestrant (ICI182780). End points included proliferation, cell signalling, cell cycle, and effect on ER-mediated transactivation. An in-vivo model of AI resistance was treated with monotherapies and combinations to assess the efficacy in delaying tumour progression. RNA-seq analysis was performed to identify changes in global gene expression as a result of the indicated therapies. Results Here, we show RAD001 and neratinib (pan-ERBB inhibitor) caused a concentration-dependent decrease in proliferation, irrespective of the ESR1 mutation status. The combination of either agent with endocrine therapy further reduced proliferation but the maximum effect was observed with a triple combination of RAD001, neratinib, and endocrine therapy. In the absence of oestrogen, RAD001 caused a reduction in ER-mediated transcription in the majority of the cell lines, which associated with a decrease in recruitment of ER to an oestrogen-response element on the TFF1 promoter. Contrastingly, neratinib increased both ER-mediated transactivation and ER recruitment, an effect reduced by the addition of RAD001. In-vivo analysis of an LTED model showed the triple combination of RAD001, neratinib, and fulvestrant was most effective at reducing tumour volume. Gene set enrichment analysis revealed that the addition of neratinib negated the epidermal growth factor (EGF)/EGF receptor feedback loops associated with RAD001. Conclusions Our data support the combination of therapies targeting ERBB2/3 and mTORC1 signalling, together with fulvestrant, in patients who relapse on endocrine therapy and retain a functional ER

Performance of the inFLUenza Patient-Reported Outcome (FLU-PRO) diary in patients with influenza-like illness (ILI)

BACKGROUND: The inFLUenza Patient Reported Outcome (FLU-PRO) measure is a daily diary assessing signs/symptoms of influenza across six body systems: Nose, Throat, Eyes, Chest/Respiratory, Gastrointestinal, Body/Systemic, developed and tested in adults with influenza. OBJECTIVES: This study tested the reliability, validity, and responsiveness of FLU-PRO scores in adults with influenza-like illness (ILI). METHODS: Data from the prospective, observational study used to develop and test the FLU-PRO in influenza virus positive patients were analyzed. Adults (≥18 years) presenting with influenza symptoms in outpatient settings in the US, UK, Mexico, and South America were enrolled, tested for influenza virus, and asked to complete the 37-item draft FLU-PRO daily for up to 14-days. Analyses were performed on data from patients testing negative. Reliability of the final, 32-item FLU-PRO was estimated using Cronbach's alpha (α; Day 1) and intraclass correlation coefficients (ICC; 2-day reproducibility). Convergent and known-groups validity were assessed using patient global assessments of influenza severity (PGA). Patient report of return to usual health was used to assess responsiveness (Day 1-7). RESULTS: The analytical sample included 220 ILI patients (mean age = 39.3, 64.1% female, 88.6% white). Sixty-one (28%) were hospitalized at some point in their illness. Internal consistency reliability (α) of FLU-PRO Total score was 0.90 and ranged from 0.72-0.86 for domain scores. Reproducibility (Day 1-2) was 0.64 for Total, ranging from 0.46-0.78 for domain scores. Day 1 FLU-PRO scores correlated (≥0.30) with the PGA (except Gastrointestinal) and were significantly different across PGA severity groups (Total: F = 81.7, p<0.001; subscales: F = 6.9-62.2; p<0.01). Mean score improvements Day 1-7 were significantly greater in patients reporting return to usual health compared with those who did not (p<0.05, Total and subscales, except Gastrointestinal and Eyes). CONCLUSIONS: Results suggest FLU-PRO scores are reliable, valid, and responsive in adults with influenza-like illness

Cloning and characterization of a novel alternatively spliced transcript of the human CHD7 putative helicase

<p>Abstract</p> <p>Background</p> <p>The <it>CHD7 </it>(Chromodomain Helicase DNA binding protein 7) gene encodes a member of the chromodomain family of ATP-dependent chromatin remodeling enzymes. Mutations in the <it>CHD7 </it>gene are found in individuals with CHARGE, a syndrome characterized by multiple birth malformations in several tissues. CHD7 was identified as a binding partner of PBAF complex (Polybromo and BRG Associated Factor containing complex) playing a central role in the transcriptional reprogramming process associated to the formation of multipotent migratory neural crest, a transient cell population associated with the genesis of various tissues. <it>CHD7 </it>is a large gene containing 38 annotated exons and spanning 200 kb of genomic sequence. Although genes containing such number of exons are expected to have several alternative transcripts, there are very few evidences of alternative transcripts associated to <it>CHD7 </it>to date indicating that alternative splicing associated to this gene is poorly characterized.</p> <p>Findings</p> <p>Here, we report the cloning and characterization by experimental and computational studies of a novel alternative transcript of the human <it>CHD7 </it>(named CHD7 CRA_e), which lacks most of its coding exons. We confirmed by overexpression of CHD7 CRA_e alternative transcript that it is translated into a protein isoform lacking most of the domains displayed by the canonical isoform. Expression of the CHD7 CRA_e transcript was detected in normal liver, in addition to the DU145 human prostate carcinoma cell line from which it was originally isolated.</p> <p>Conclusions</p> <p>Our findings indicate that the splicing event associated to the CHD7 CRA_e alternative transcript is functional. The characterization of the CHD7 CRA_e novel isoform presented here not only sets the basis for more detailed functional studies of this isoform, but, also, contributes to the alternative splicing annotation of the <it>CHD7 </it>gene and the design of future functional studies aimed at the elucidation of the molecular functions of its gene products.</p