Letter To The Editor: “Impact of ACE Gene Polymorphisms on the Progression of IgA Nephropathy in India”

Tubulointerstitial involvement is well recognized in systemic lupus erythematosus. The tubular dysfunction is usually latent and usually presents after diagnosis of systemic lupus erythematosus. We report a case presenting that she is well previously and initially diagnosed as periodic paralysis of hypokalemia at emergency room and final diagnosis is systemic lupus erythematosus with H⁺-ATPase pump defect of distal type renal tubular acidosis. Kidney biopsy showed lupus nephritis classified as mesangial proliferative glomerulonephritis WHO class II B. Her renal tubular acidosis was subsided after steroid therapy was administered.     

Role of microRNA29b in blood–brain barrier dysfunction during hyperhomocysteinemia: an epigenetic mechanism

Although blood–brain barrier (BBB) integrity is maintained by the cross-talk of endothelial cells, junction proteins, and neurogliovascular network, the epigenetic mechanisms behind BBB permeability are largely unknown. We are reporting for the first time miR29b-mediated regulation of BBB, which is a novel mechanism underlying BBB integrity. We hypothesize that miR29b regulates BBB dysfunction by regulating DNMT3b, which consequently regulates the levels of metalloproteinases, that can eat up the membrane and junction proteins leading to leaky vasculature. In addition, 5′-azacytidine (5′-aza) was used to test its efficacy on BBB permeability. Blood–brain barrier disruption model was created by using homocysteine, and in the models miR29b was identified to be most affected, by using microRNA RT²-qPCR array. MiR29b mimics and inhibitors also confirmed that miR29b regulates the levels DNMT3b and MMP9. In hyperhomocysteinemic cystathionine-β-synthase deficient (CBS^+/−) mice with high brain vessel permeability, miR29b levels were also high as compared with wild-type (WT) mice. Interestingly, 5′-aza improved BBB permeability by decreasing the expression of miR29b. In conclusion, our data suggested miR29b-mediated regulation of BBB dysfunction through DNMT3b and MMP9. It also potentiates the use of microRNAs as candidates for future epigenetic therapies in the improvement of BBB integrity.     

A systematic evaluation of Schwann cell injection into acellular cold-preserved nerve grafts

Peripheral nerve regeneration after injury depends on environmental cues and trophic support. Schwann cells (SCs) secrete trophic factors that promote neuronal survival and help guide axons during regeneration. The addition of SCs to acellular nerve grafts is a promising strategy for enhancing peripheral nerve regeneration; however, inconsistencies in seeding parameters have led to varying results. The current work sought to establish a systematic approach to seeding SCs in cold-preserved acellular nerve grafts. Studies were undertaken to (1) determine the needle gauge for optimal cell survival and minimal epineurial disruption during injection, (2) track the seeded SCs using a commercially available dye, and (3) evaluate the seeding efficiency of SCs in nerve grafts. It was determined that seeding with a 27-gauge needle resulted in the highest viability of SCs with the least damage to the epineurium. In addition, Qtracker(?) dye, a commercially available quantum dot nanocrystal, was used to label SCs prior to transplantation, which allowed visualization of the seeded SCs in nerve grafts. Finally, stereological methods were used to evaluate the seeding efficiency of SCs in nerve grafts immediately after injection and following a 1- or 3-day in vitro incubation in SC growth media. Using a systematic approach, the best needle gauge and a suitable dye for SC visualization in acellular nerve grafts were identified. Seeding efficiency in these grafts was also determined. The findings will lead to improvements ability to assess injection of cells (including SCs) for use with acellular nerve grafts to promote nerve regeneration.     

The impact and utility of encounter patient decision aids: Systematic review,meta-analysis and narrative synthesis

Objective

To determine the effect of encounter patient decision aids (PDAs) as evaluated in randomized controlled trials (RCTs) and conduct a narrative synthesis of non-randomized studies assessing feasibility, utility and their integration into clinical workflows.

Biostatistics Series Module 2: Overview of Hypothesis Testing

Hypothesis testing (or statistical inference) is one of the major applications of biostatistics. Much of medical research begins with a research question that can be framed as a hypothesis. Inferential statistics begins with a null hypothesis that reflects the conservative position of no change or no difference in comparison to baseline or between groups. Usually, the researcher has reason to believe that there is some effect or some difference which is the alternative hypothesis. The researcher therefore proceeds to study samples and measure outcomes in the hope of generating evidence strong enough for the statistician to be able to reject the null hypothesis. The concept of the P value is almost universally used in hypothesis testing. It denotes the probability of obtaining by chance a result at least as extreme as that observed, even when the null hypothesis is true and no real difference exists. Usually, if P is < 0.05 the null hypothesis is rejected and sample results are deemed statistically significant. With the increasing availability of computers and access to specialized statistical software, the drudgery involved in statistical calculations is now a thing of the past, once the learning curve of the software has been traversed. The life sciences researcher is therefore free to devote oneself to optimally designing the study, carefully selecting the hypothesis tests to be applied, and taking care in conducting the study well. Unfortunately, selecting the right test seems difficult initially. Thinking of the research hypothesis as addressing one of five generic research questions helps in selection of the right hypothesis test. In addition, it is important to be clear about the nature of the variables (e.g., numerical vs. categorical; parametric vs. nonparametric) and the number of groups or data sets being compared (e.g., two or more than two) at a time. The same research question may be explored by more than one type of hypothesis test. While this may be of utility in highlighting different aspects of the problem, merely reapplying different tests to the same issue in the hope of finding a P < 0.05 is a wrong use of statistics. Finally, it is becoming the norm that an estimate of the size of any effect, expressed with its 95% confidence interval, is required for meaningful interpretation of results. A large study is likely to have a small (and therefore “statistically significant”) P value, but a “real” estimate of the effect would be provided by the 95% confidence interval. If the intervals overlap between two interventions, then the difference between them is not so clear-cut even if P < 0.05. The two approaches are now considered complementary to one another.     

COVID-19 prediction models: a systematic literature review

As the world grapples with the problem of the coronavirus disease 2019 (COVID-19) pandemic and its devastating effects, scientific groups are working towards solutions to mitigate the effects of the virus. This paper aimed to collate information on COVID-19 prediction models. A systematic literature review is reported, based on a manual search of 1,196 papers published from January to December 2020. Various databases such as Google Scholar, Web of Science, and Scopus were searched. The search strategy was formulated and refined in terms of subject keywords, geographical purview, and time period according to a predefined protocol. Visualizations were created to present the data trends according to different parameters. The results of this systematic literature review show that the study findings are critically relevant for both healthcare managers and prediction model developers. Healthcare managers can choose the best prediction model output for their organization or process management. Meanwhile, prediction model developers and managers can identify the lacunae in their models and improve their data-driven approaches.     

Phase II Trial of Imatinib Maintenance Therapy After Irinotecan and Cisplatin in Patients With c-Kit–Positive,Extensive-Stage Small-Cell Lung Cancer

BackgroundThe prognosis for patients with extensive-stage small-cell lung cancer remains poor. This trial was designed to evaluate irinotecan/cisplatin plus maintenance imatinib in patients with c-Kit–positive disease (the transmembrane receptor c-Kit is the product of the c-KIT protooncogene).Patients and MethodsImmunohistochemistry for c-Kit was performed before enrollment. Treatment consisted of irinotecan 65 mg/m² on days 1 and 8 plus cisplatin 60 mg/m² on day 1 and every 21 days for 4 cycles. Imatinib was administered at 400 mg twice a day until progression or unacceptable toxicity occurred.ResultsFourteen patients were enrolled. Slow accrual led to early study termination. Six patients did not begin treatment with imatinib because of disease progression, persistent toxicity, or referral for radiation therapy. Eight patients had a partial response with irinotecan/cisplatin and received imatinib. The median number of weeks on imatinib was 6.1 (range, 4.1-25.1 weeks). Reasons for imatinib discontinuation included disease progression (n = 7) and persistent neutropenia (n = 1). No objective responses to imatinib were evident, but 3 patients (21%) exhibited stable disease for 12, 15, and 25 weeks. The median progression-free survival was 4.3 months (95% CI, 2.9-4.8 months). The median overall survival was 7.8 months (95% CI, 5.7-10.0 months). The irinotecan/cisplatin regimen was well tolerated (grade 1/2 neutropenia, 29%; anemia, 43%; thrombocytopenia, 14%; and diarrhea, 29%), except in 1 patient with grade 3 vomiting. Imatinib toxicity included grade 1/2 nausea in 50% of the patients, peripheral edema in 75% of the patients, grade 3 fatigue in 13% of the patients, and neutropenia in 13% of the patients.ConclusionDespite the selection of tumors expressing c-Kit, imatinib did not appear to delay disease progression after response to chemotherapy. However, this trial was underpowered because of its early termination. Although disease stability with imatinib was evident in 3 patients and the therapy was well tolerated, this approach does not appear to warrant further clinical study.     

Clinical Determinants of Durable Clinical Benefit of Pembrolizumab in Veterans With Advanced Non–Small-Cell Lung Cancer

Background

Because of the prevalence of smoking in the veteran population, non–small-cell lung cancer (NSCLC) remains a significant cause of morbidity and mortality. The objectives of our study were to evaluate the extent of durable clinical benefit (DCB) to pembrolizumab in veterans with metastatic NSCLC and to identify clinical determinants of DCB.