Clinico-radiological and bronchoscopic predictors of microbiological yield in sputum negative tuberculosis in Pakistan.

To determine association of clinico-radiological factors and radiological activity with diagnostic yield in sputum-smear negative tuberculosis (TB). Prospective observational study in the Military Hospital Rawalpindi (Pakistan) from July to December 2018. Adult patients having no contraindications to bronchoscopy were included. HIV positive patients and those on anti-tuberculosis therapy for more than one week were excluded. High-resolution computed tomography (HRCT) findings were classified based on active and inactive tuberculosis features. Washings were sent for acid-fast bacillus (AFB) smear, GeneXpert assay and cultures. Out of 215 patients, 42.3% (91) were diagnosed with microbiological or histological evidence of TB. On univariate analysis, cavitation (p-value <0.001), soft-tissue nodules (p-value 0.04), and endobronchial mucosal changes (p-value 0.02) were associated with culture positivity. Presence of cavitation (OR= 4.10; CI= 2.18,7.73; p-value<0.001) was the only independent predictor of microbiological yield. Diagnostic yield was 70%, 50%, 12.5% and 8.6% in patients with definitely active, probably active, indeterminate and inactive tuberculosis HRCT features respectively. Sensitivity, specificity, positive predictive value and negative predictive value of HRCT active TB were 95.38% (95% CI 87.10-99.04), 48.00 % (95% CI 39.78-56.30), 44.29% (95% CI 40.31-48.33), 96.00 % (95%CI 88.70-98.66) respectively. There was no significant association between age groups, smoking status and gender with diagnosis of tuberculosis in our study. Radiological activity and certain visualized bronchoscopic changes were associated with good diagnostic performance and can be used as predictive factors in diagnosis of active smear negative tuberculosis.

On p53 revival using system oriented drug dosage design.

We propose a new paradigm in the drug design for the revival of the p53 pathway in cancer cells. It is shown that the current strategy of using small molecule based Mdm2 inhibitors is not enough to adequately revive p53 in cancerous cells, especially when it comes to the extracting pulsating behavior of p53. This fact has come to notice when a novel method for the drug dosage design is introduced using system oriented concepts. As a test case, small molecule drug Mdm2 repressor Nutlin 3a is considered. The proposed method determines the dose of Nutlin to revive p53 pathway functionality. For this purpose, PBK dynamics of Nutlin have also been integrated with p53 pathway model. The p53 pathway is the focus of researchers for the last thirty years for its pivotal role as a frontline cancer suppressant protein due to its effect on cell cycle checkpoints and cell apoptosis in response to a DNA strand break. That is the reason for finding p53 being absent in more than 50% of tumor cancers. Various drugs have been proposed to revive p53 in cancer cells. Small molecule based drugs are at the foremost and are the subject of advanced clinical trials. The dosage design of these drugs is an important issue. We use control systems concepts to develop the drug dosage so that the cancer cells can be treated in appropriate time. We investigate by using a computational model how p53 protein responds to drug Nutlin 3a, an agent that interferes with the MDM2-mediated p53 regulation. The proposed integrated model describes in some detail the regulation network of p53 including the negative feedback loop mediated by MDM2 and the positive feedback loop mediated by Mdm2 mRNA as well as the reversible represses of MDM2 caused by Nutlin. The reported PBK dynamics of Nutlin 3a are also incorporated to see the full effect. It has been reported that p53 response to stresses in two ways. Either it has a sustained (constant) p53 response, or there are oscillations in p53 concentration. The claimed dosage strategy achieves the p53 response in the first case. However, for the induction of oscillations, it is shown through bifurcation analysis that to achieve oscillating behavior of p53 inhibition of Mdm2 is not enough, rather antirepression of the p53-Mdm2 complex is also needed which leads to the need of a new drug design paradigm.

Optimization-Based Economical Flexural Design of Singly Reinforced Concrete Beams: A Parametric Study.

In the past, many studies have been conducted on the optimization of reinforced concrete (RC) structures. These studies have demonstrated the effectiveness of different optimization techniques to obtain an economical design. However, the use of optimization techniques to an obtain economical design is not so practical due to the difficulty in applying most of the optimization techniques to achieve an optimal solution. The RC beam is one of the most common structural elements encountered by a practising design engineer. The current study is designed to highlight the potential of the Solver tool in MS Excel as an easy-to-use option for optimizing the design of simply supported RC beams. A user-friendly interface was developed in a spreadsheet in which beam design parameters from a typical design can be entered and an economical design can be obtained using the Evolutionary Algorithm available in the MS Excel Solver tool. To demonstrate the effectiveness of the developed optimization tool, three examples obtained from the literature have been optimized. The results showed that up to 24% economical solution can be obtained by keeping the same material strengths that were assumed in the original design. However, if material strength is also considered as a variable, up to 44% of the economical solution can be obtained. A parametric study was also conducted to investigate the effect of different design variables on the economical design of simply supported RC beams and to derive useful rules of thumb for their design and proportioning, with the objective of cost minimization. The results of the parametric study suggest that the grade of the reinforcing steel is one of the most influential factors that affect the cost of simply supported RC beams. Practicing engineers can use the trends derived from this research to further refine their optimal designs.

Clearing the Fog: Is Hydroxychloroquine Effective in Reducing Coronavirus Disease-2019 Progression? A Randomized Controlled Trial.

Background Hydroxychloroquine (HCQ) has been considered for the treatment of coronavirus disease 2019 (COVID-19), but data on its efficacy are conflicting. We analyzed the efficacy of HCQ along with standard of care (SOC) treatment, compared with SOC alone, in reducing disease progression in mild COVID-19. Methods A single-center open-label randomized controlled trial was conducted from April 10 to May 31, 2020 at Pak Emirates Military Hospital, Rawalpindi. Five hundred patients of both genders between the ages of 18 and 80 years with mild COVID-19 were enrolled in the study. A total of 349 patients were assigned to the intervention group (standard dose of HCQ plus SOC) and 151 patients were assigned to SOC only. The primary outcome was progression of disease while secondary outcome was polymerase chain reaction (PCR) negativity on days 7 and 14. The results were analyzed on Statistical Package for Social Sciences (SPSS; IBM Corp., Armonk, NY) version 23. A p-value <0.05 was considered significant.  Results The median age of the intervention group was 34 ± 11.778 years and control group was 34 ± 9.813 years. Disease progressed in 16 patients, 11 (3.15%) of which were in the intervention group and 5 (3.3%) in the control group (p-value = 0.940). PCR negative cases in intervention and control groups on day 7 were 182 (52.1%) and 54 (35.8%), respectively (p-value = 0.001); and on day 14 were 244 (69.9%) and 110 (72.9%), respectively (p-value = 0.508). Consecutive PCR negativity on days 7 and 14 was observed in 240 (68.8%) patients in the intervention group compared to 106 (70.2%) in the control group (p-value = 0.321). Conclusion The addition of HCQ to SOC in hospitalized mild COVID-19 patients neither stops disease progression nor helps in early and sustained viral clearance.

Therapeutic plasma exchange for coronavirus disease-2019 triggered cytokine release syndrome; a retrospective propensity matched control study.

BACKGROUND: Cytokine release syndrome (CRS) plays a pivotal role in the pathophysiology and progression of Coronavirus disease-2019 (COVID-19). Therapeutic plasma exchange (TPE) by removing the pathogenic cytokines is hypothesized to dampen CRS. OBJECTIVE: To evaluate the outcomes of the patients with COVID-19 having CRS being treated with TPE compared to controls on the standard of care. METHODOLOGY: Retrospective propensity score-matched analysis in a single centre from 1st April to 31st July 2020. We retrospectively analyzed data of 280 hospitalized patients developing CRS initially. PSM was used to minimize bias from non-randomized treatment assignment. Using PSM 1:1, 90 patients were selected and assigned to 2 equal groups. Forced matching was done for disease severity, routine standard care and advanced supportive care. Many other Co-variates were matched. Primary outcome was 28 days overall survival. Secondary outcomes were duration of hospitalization, CRS resolution time and timing of viral clearance on Polymerase chain reaction testing. RESULTS: After PS-matching, the selected cohort had a median age of 60 years (range 32-73 in TPE, 37-75 in controls), p = 0.325 and all were males. Median symptoms duration was 7 days (range 3-22 days' TPE and 3-20 days controls), p = 0.266. Disease severity in both groups was 6 (6.6%) moderate, 40 (44.4%) severe and 44 (49%) critical. Overall, 28-day survival was significantly superior in the TPE group (91.1%), 95% CI 78.33-97.76; as compared to PS-matched controls (61.5%), 95% CI 51.29-78.76 (log rank 0.002), p<0.001. Median duration of hospitalization was significantly reduced in the TPE treated group (10 days vs 15 days) (p< 0.01). CRS resolution time was also significantly reduced in the TPE group (6 days vs. 12 days) (p< 0.001). In 71 patients who underwent TPE, the mortality was 0 (n = 43) if TPE was done within the first 12 days of illness while it was 17.9% (deaths 5, n = 28 who received it after 12th day (p = 0.0045). CONCLUSION: An earlier use of TPE was associated with improved overall survival, early CRS resolution and time to discharge compared to SOC for COVID-19 triggered CRS in this selected cohort of PS-matched male patients from one major hospital in Pakistan.