Outcome of early use of non-invasive positive pressure ventilation in patients with acute exacerbation of chronic obstructive pulmonary disease.

OBJECTIVE: To determine the outcome of early use of non-invasive positive pressure ventilation (NIPPV) in Pakistani patients with acute exacerbation of chronic obstructive pulmonary disease. METHODS: This descriptive study was conducted at Shifa International Hospital Islamabad from April 2015 to January 2017. A total of 120 patients with acute exacerbation of chronic obstructive pulmonary disease receiving NIPPV alongside standard therapy were included in the study. The patients were clinically assessed before starting on NIPPV. The parameters of respiratory rate, pH and paCO2 were monitored and NIPPV was given for six hours to evaluate clinical outcomes and analyze the factors predicting failure (requirement of mechanical ventilation and mortality). Frequency and percentages were calculated for qualitative variables while Mean and Standard Deviation for quantitative variables. Chi-square and t-test were used to see differences in pre and post NIPPV arterial blood gases. RESULTS: Patients' mean age was 58.88±10.09 years. Males were 88 (73.3%) and females were 32 (26.7%). The mean respiratory rate was 24±1.45 per minute before and 17.96±1.35 per minute after NIPPV (p < 0.00001). The mean pH before NIPPV was 7.27±0.04 and afterwards 7.38±0.02 (p < 0.00001). The mean pCO2 was 61.87±9.60 mm of Hg before and 57.46±6.79 mm of Hg after NIPPV (P < 0.0003). Twenty Four (20%) patients required invasive ventilation of which 19 (15.8%) patients could not survive. CONCLUSIONS: There was remarkable improvement in the arterial blood gases after NIPPV. However, the high mortality rate and significant number of COPD patients requiring mechanical ventilation necessitates further investigation into our population.

Perceptions and attitudes towards research amongst medical students at Shifa College of Medicine.

OBJECTIVE: To understand medical students' perceptions and attitudes towards research to help facilitators design specific courses according to their needs. METHODS: The cross-sectional study was conducted at Shifa College of Medicine, Islamabad, Pakistan, from May to November 2013, and comprised undergraduate medical students. A pre-tested questionnaire was used for data collection. Students' response was recorded on a Likert scale from 'strongly disagree' 1 to 'strongly agree' 5. Analysis was done using statistical SPSS17. RESULTS: Of the 195 students enrolled, 172(88%) responded. Overall, 78(45.3%) students said they were aware of research. Research was considered useful for their professional careers and relevant to their daily life by 133(65.7%) students, while 72(41.9%) did not consider it worthwhile to pursue research as a career. Besides, 71(41.3%) students enjoyed research, while 120(70%) perceived research as stressful and 107(62.2) complex. CONCLUSIONS: Most students considered research valuable but at the same time they perceived it as stressful and complex.

Rheumatoid arthritis: the importance of evidence based diagnostic reasoning in preventing debilitating consequences.

BACKGROUND: The early diagnosis of Rheumatoid arthritis can improve clinical outcomes, in terms of morbidity and mortality. This study evaluates the role of evidence informed diagnostic reasoning in the early diagnosis of Rheumatoid arthritis. METHODS: A cross-sectional survey was conducted on 200 respondents inclusive of doctors and medical students, at Shifa college of Medicine, Islamabad from April to December 2010. A questionnaire with three common clinical scenarios of low, intermediate and high pre-test probability for rheumatoid arthritis (RA) was provided to the respondents. The differences between the reference and respondents' estimates of pre and post-test probability were used to assess the respondents' clinical diagnostic reasoning process, as a tool to diagnose RA early. Respondents were also enquired about the cost effectiveness or potential harms of Rheumatoid factor (RF). Consecutive sampling technique was used and the data was analysed using SPSS-15. RESULTS: In all scenarios, the pre-test probability was estimated close to the reference estimates suggesting respondents' ability to rule in or rule out the disease. However, some over-estimation of the pre-test probability was noticed in low and intermediate pre-test probability settings. Post-test probabilities were significantly underestimated reflecting their inability to calculate post-test probabilities in all scenarios. More tests were ordered as the disease probability increased. Most respondents were of the opinion that RF is cost effective and safe. CONCLUSIONS: The significant underestimation of the post-test probability necessitates more emphasis on Bayesian probabilistic thinking in clinical practice to facilitate early diagnosis of rheumatoid arthritis.

Impact of probability estimation on frequency of urine culture requests in ambulatory settings.

OBJECTIVE: To determine the perceptions of the medical community about urine culture in diagnosing urinary tract infections. METHODS: The cross-sectional survey based of consecutive sampling was conducted at Shifa International Hospital, Islamabad, on 200 doctors, including medical students of the Shifa College of Medicine, from April to October 2010. A questionnaire with three common clinical scenarios of low, intermediate and high pre-test probability for urinary tract infection was used to assess the behaviour of the respondents to make a decision for urine culture test. The differences between the reference estimates and the respondents' estimates of pre- and post-test probability were assessed. The association of estimated probabilities with the number of tests ordered was also evaluated. The respondents were also asked about the cost effectiveness and safety of urine culture and sensitivity. Data was analysed using SPSS version 15. RESULTS: In low pre-test probability settings, the disease probability was over-estimated, suggesting the participants' inability to rule out the disease. The post-test probabilities were, however, under-estimated by the doctors as compared to the students. In intermediate and high pre-test probability settings, both over- and underestimation of probabilities were noticed. Doctors were more likely to consider ordering the test as the disease probability increased. Most of the respondents were of the opinion that urine culture was a cost-effective test and there was no associated potential harm. CONCLUSIONS: The wide variation in the clinical use of urine culture necessitates the formulation of appropriate guidelines for the diagnostic use of urine culture, and application of Bayesian probabilistic thinking to real clinical situations.

NOTCH pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts.

Cancer stem cells (CSCs) are thought to be critical for the engraftment and long-term growth of many tumors, including glioblastoma (GBM). The cells are at least partially spared by traditional chemotherapies and radiation therapies, and finding new treatments that can target CSCs may be critical for improving patient survival. It has been shown that the NOTCH signaling pathway regulates normal stem cells in the brain, and that GBMs contain stem-like cells with higher NOTCH activity. We therefore used low-passage and established GBM-derived neurosphere cultures to examine the overall requirement for NOTCH activity, and also examined the effects on tumor cells expressing stem cell markers. NOTCH blockade by gamma-secretase inhibitors (GSIs) reduced neurosphere growth and clonogenicity in vitro, whereas expression of an active form of NOTCH2 increased tumor growth. The putative CSC markers CD133, NESTIN, BMI1, and OLIG2 were reduced following NOTCH blockade. When equal numbers of viable cells pretreated with either vehicle (dimethyl sulfoxide) or GSI were injected subcutaneously into nude mice, the former always formed tumors, whereas the latter did not. In vivo delivery of GSI by implantation of drug-impregnated polymer beads also effectively blocked tumor growth, and significantly prolonged survival, albeit in a relatively small cohort of animals. We found that NOTCH pathway inhibition appears to deplete stem-like cancer cells through reduced proliferation and increased apoptosis associated with decreased AKT and STAT3 phosphorylation. In summary, we demonstrate that NOTCH pathway blockade depletes stem-like cells in GBMs, suggesting that GSIs may be useful as chemotherapeutic reagents to target CSCs in malignant gliomas.

Knowledge, attitudes and practices of type 2 diabetic patients.

BACKGROUND: Education is the cornerstone of diabetes care. Because of lack of awareness, most patients suffer from diabetes complications. This study was conducted to determine the knowledge, attitudes and practices among patients with type 2 diabetes. METHODS: This descriptive study included one hundred type 2 diabetics. Patients were interviewed using a structured questionnaire. The mean age of the patients was 50 +/- 5 years with the male to female ratio being 1:3. The data was collected using convenience sampling technique and analyzed using statistical package Epi Info 6.0. The patients knowledge about the disease, their attitudes and practices were the main outcome measures. RESULTS: In our study, patients' awareness about diabetes was low. The mean of correct answers for glycemic control risk factors and complications was 33.5%, 69% and 39% respectively. Sixty-one percent of the patients regularly checked blood sugar but only few knew target blood glucose values. Only one sixth of all the patients could correctly answer question regarding nutrition. 92% recognized blood pressure as a risk factor while the correct answers for hyperlipedimia, cigarette smoking, sedentary life style and body weight were 42%, 70%, 76% and 66% respectively. Awareness about eye and renal complications was also quite low. Doctors were the main source of information available to the test population. CONCLUSIONS: The knowledge, attitude and practice scores were low in most areas of diabetes care emphasising the need for additional educational efforts.

Association of Hypertension with Non-HDL Cholesterol in Patients with Type 2 Diabetes Mellitus.

OBJECTIVE: To determine the association of hypertension with Non-HDL Cholesterol (Non-HDL.C) among patients with type 2 diabetes mellitus. STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY:  Shifa Foundation Community Health Centre, Shifa International Hospital, Islamabad, from January to December 2019. METHODOLOGY:  This study comprised of 214 patients with type 2 diabetes. Detailed history, examination, anthropometric measurements, fasting lipid profiles and blood glucose levels were recorded for all patients. Non-HDL.C was determined in all patients by subtracting HDL Cholesterol (HDL.C) from total Cholesterol (Total.C). Association of hypertension with Non-HDL.C was analysed using Chi-square Fisher Exact test for qualitative data and post-stratification t-test for quantitative data. Correlation of rising levels of Non-HDL.C with Total.C, LDL.C, Triglycerides, HDL.C and fasting blood sugar was analysed using ANOVA. SPSS version 23 was used for statistical analysis. RESULTS: Non-HDL.C was raised in 169 (78.97%) patients with type 2 diabetes. However, there was no significant difference in the mean Non-HDL.C among patients with hypertension and without hypertension (156.35 +38.52 mg/dl versus 156.81 +45.82 mg/dl; p = 0.936). Furthermore, there was no significant difference in the Total.C, LDL.C, Triglycerides and the number of patients with raised Non-HDL.C among both groups. Increasing values of Non-HDL.C correlated significantly to Total.C, LDL.C and Triglycerides (p <0.001). CONCLUSION: Hypertension had no significant association with Non-HDL.C in patients with type 2 diabetes. However, the raised level of Non-HDL.C in majority of type 2 diabetic patients in addition to significant correlation with Total.C, LDL.C and Triglycerides necessitates its screening irrespective of the blood pressure status. Key Words: Non-HDL cholesterol, Dyslipidemia, Diabetes, Hypertension.

Amino Acid Mutations in NS5B Protein among Treatment-naive Genotype 3A Infected Patients.

OBJECTIVE: To determine the frequency of mutations at specific amino acid positions in full length NS5B gene among chronic HCV genotype 3a infected patients of Peshawar, who had not taken any previous treatment. STUDY DESIGN: Cross-sectional descriptive study. PLACE AND DURATION OF STUDY: Institute of Basic Medical Sciences, Khyber Medical University, Peshawar (IBMS, KMU) and Comsats Institute of Information Technology (CIIT), Islamabad from September 2016 to December 2017. METHODOLOGY: HCV genotype determination was carried out among 310 actively infected, treatment-naive patients, using type specific PCR-based genotyping assay. In a total of 162 (52%) HCV genotype 3a isolates, NS5B gene was amplified in 126 (78%) samples using qualitative PCR and sequencing. NS5B gene sequences were analysed for clinically relevant mutations against standard HCV 3a reference sequence (Isolate NZL1, BAA04609) using MEGA 6 software. RESULTS: Analysis of HCV NS5B amino acid sequences (aa.1-591), comprising essential motif A-F revealed four novel mutations: A67V, T131I, R374H and M425L in 27 (21%) viral isolates. Mutation D/N244S and D/N310K were found in 14 (11%) of the pre-treatment isolates. Mutations at positions 282 and 316 (S282T and C316N/Y) were not identified among studied isolates. CONCLUSION: This study reports mutations based on complete NS5B protein of HCV 3a genome that could help predict treatment response among the chronically infected with HCV genotype 3a patients of Peshawar.

Association of Impaired Fasting Glucose with Hypertension.

OBJECTIVE: To evaluate the association of impaired fasting glucose (IFG) with hypertension in Pakistani population. STUDY DESIGN: A cross-sectional, analytical study. PLACE AND DURATION OF STUDY: Shifa Community Health Centre, Islamabad from December 2016 to July 2017. METHODOLOGY: One hundred and eighty-seven hypertensive patients were included in the study, using consecutive sampling technique. Demographic, anthropometric, and laboratory data of the patients were recorded. Continuous variables were expressed as mean + SD and categorical variables as numbers and percentages. Differences among males/females and between hypertensive patients with normal, impaired fasting glucose and diabetes for risk factors were analysed, using independent sample t-test, ANOVA and chi-square test using SPSS version 24. RESULTS: The mean age of patients was 52.98 +11.22 years. Females were 69.9% and males 30.1%. The total frequency of IFG in patients with hypertension was 42.6% and new onset diabetes 12.5% showing its close association with hypertension. There was no significant difference between males and females for risk factors (age, BMI, blood pressure, total cholesterol, LDL-cholesterol, and HDL-cholesterol) except for more education, smoking, and high triglyceride in males. There was no significant difference among hypertensive patients with normal, impaired fasting glucose and diabetes for risk factors (gender, BMI, blood pressure, total cholesterol, LDL-cholesterol, triglycerides, HDL-cholesterol and family history) except for smoking. CONCLUSION: The significant association of impaired fasting glucose with hypertension necessitates early screening for impaired fasting glucose.

A novel chordoma xenograft allows in vivo drug testing and reveals the importance of NF-κB signaling in chordoma biology.

Chordoma is a rare primary bone malignancy that arises in the skull base, spine and sacrum and originates from remnants of the notochord. These tumors are typically resistant to conventional chemotherapy, and to date there are no FDA-approved agents to treat chordoma. The lack of in vivo models of chordoma has impeded the development of new therapies for this tumor. Primary tumor from a sacral chordoma was xenografted into NOD/SCID/IL-2R γ-null mice. The xenograft is serially transplantable and was characterized by both gene expression analysis and whole genome SNP genotyping. The NIH Chemical Genomics Center performed high-throughput screening of 2,816 compounds using two established chordoma cell lines, U-CH1 and U-CH2B. The screen yielded several compounds that showed activity and two, sunitinib and bortezomib, were tested in the xenograft. Both agents slowed the growth of the xenograft tumor. Sensitivity to an inhibitor of IκB, as well as inhibition of an NF-κB gene expression signature demonstrated the importance of NF-κB signaling for chordoma growth. This serially transplantable chordoma xenograft is thus a practical model to study chordomas and perform in vivo preclinical drug testing.

The clinical diagnostic reasoning process determining the use of endoscopy in diagnosing peptic ulcer disease.

OBJECTIVE: To evaluate the clinical diagnostic reasoning process as a tool to decrease the number of unnecessary endoscopies for diagnosing peptic ulcer disease. tudy DESIGN: Cross-sectional KAP study. PLACE AND DURATION OF STUDY: Shifa College of Medicine, Islamabad, from April to August 2010. METHODOLOGY: Two hundred doctors were assessed with three common clinical scenarios of low, intermediate and high pre-test probability for peptic ulcer disease using a questionnaire. The differences between the reference estimates and the respondents' estimates of pre-test and post test probability were used for assessing the ability of estimating the pretest probability and the post test probability of the disease. Doctors were also enquired about the cost-effectiveness and safety of endoscopy. Consecutive sampling technique was used and the data was analyzed using SPSS version 16. RESULTS: In the low pre-test probability settings, overestimation of the disease probability suggested the doctors' inability to rule out the disease. The post test probabilities were similarly overestimated. In intermediate pre-test probability settings, both over and under estimation of probabilities were noticed. In high pre-test probability setting, there was no significant difference in the reference and the responders' intuitive estimates of post test probability. Doctors were more likely to consider ordering the test as the disease probability increased. Most respondents were of the opinion that endoscopy is not a cost-effective procedure and may be associated with a potential harm. CONCLUSION: Improvement is needed in doctors' diagnostic ability by more emphasis on clinical decision-making and application of bayesian probabilistic thinking to real clinical situations.

High ALDH activity identifies chemotherapy-resistant Ewing's sarcoma stem cells that retain sensitivity to EWS-FLI1 inhibition.

BACKGROUND: Cancer stem cells are a chemotherapy-resistant population capable of self-renewal and of regenerating the bulk tumor, thereby causing relapse and patient death. Ewing's sarcoma, the second most common form of bone tumor in adolescents and young adults, follows a clinical pattern consistent with the Cancer Stem Cell model - remission is easily achieved, even for patients with metastatic disease, but relapse remains frequent and is usually fatal. METHODOLOGY/PRINCIPAL FINDINGS: We have isolated a subpopulation of Ewing's sarcoma cells, from both human cell lines and human xenografts grown in immune deficient mice, which express high aldehyde dehydrogenase (ALDH(high)) activity and are enriched for clonogenicity, sphere-formation, and tumor initiation. The ALDH(high) cells are resistant to chemotherapy in vitro, but this can be overcome by the ATP binding cassette transport protein inhibitor, verapamil. Importantly, these cells are not resistant to YK-4-279, a small molecule inhibitor of EWS-FLI1 that is selectively toxic to Ewing's sarcoma cells both in vitro and in vivo. CONCLUSIONS/SIGNIFICANCE: Ewing's sarcoma contains an ALDH(high) stem-like population of chemotherapy-resistant cells that retain sensitivity to EWS-FLI1 inhibition. Inhibiting the EWS-FLI1 oncoprotein may prove to be an effective means of improving patient outcomes by targeting Ewing's sarcoma stem cells that survive standard chemotherapy.