Two by Two Factorial Design using Metformin and Curcumin for Second Primary Head and Neck Cancer Prevention Trial.

OBJECTIVE: The 2x2 factorial design is an effective method that allows for multiple comparisons, especially in the context of interactions between different interventions, without substantially increasing the required sample size. In view of the considerable preclinical evidence for Curcumin and Metformin in preventing the development and progression of head and neck squamous cell carcinoma (HNSCC), this study describes the protocol of the clinical trial towards applying the drug combination in prevention of second primary tumors. METHODS: We have applied the trial design to a large phase IIB/III double-blind, multi-centric, placebo-controlled, randomized clinical trial to determine the safety and efficacy of Metformin and Curcumin in the prevention of second primary tumours (SPT) of the aerodigestive tract following treatment of HNSCC (n=1,500) [Clinical Registry of India, CTRI/2018/03/012274]. Patients recruited in this trial will receive Metformin (with placebo), Curcumin (with placebo), Metformin, and Curcumin or placebo alone for a period of 36 months. The primary endpoint of this trial is the development of SPT, while the secondary endpoints are toxicities associated with the agents, incidence of recurrence, and identifying potential biomarkers. In this article, we discuss the 2x2 factorial design and how it applies to the head and neck cancer chemoprevention trial. CONCLUSION: 2x2 factorial design is an effective trial design for chemoprevention clinical trials where the effectiveness of multiple interventions needs to be tested parallelly.

Prognostic Impact of Poor Differentiation of Squamous Cell Carcinoma in Treatment Naïve Node-Negative Early Oral Cancers.

We have conducted this study to understand the impact of poor differentiation (PD), as a sole poor prognostic factor, in early oral cancers. This was a retrospective analysis of a prospectively maintained database of clinically node-negative early T stage OSCC patients operated between 2012 and 2014. Impact of PD on the survival and role of adjuvant therapy in these patients was noted. Out of 1172 patients screened, 280 patients were found to be eligible for the study. 11.4% patients had PDSCC. It was found to be associated with tongue cancers and peri-neural invasion. It had a significant impact on OS and DFS (48.7 months vs 81.4 months, p < 0.00 and 44.6 months vs 73.5 months, p < 0.00 respectively. Hazard ratio for DFS: 4.08. Although patients with PDSCC had better survival with radiotherapy, but this was not statistically significant. Poor differentiation as a stand-alone factor impacts survival in patients with early oral cancer. It may be seen more often in patients with tongue cancer and may have associated PNI. The role of adjuvant therapy in such patients is not clear.

A strategy for evaluation of isotopic enrichment and structural integrity of deuterium labelled compounds by using HR-MS and NMR.

Determining the purity of deuterium labelled compounds is important due to the increasing use of these compounds in mass spectrometry (MS) based quantitative analyses for targeting metabolic flux, reducing toxicity, confirming reaction mechanisms during synthesis, predicting enzyme mechanisms, and enhancing the efficacy of drugs, in quantitative proteomics, and also as internal standards. In the present study, a strategy using liquid chromatography electrospray ionization high resolution mass spectrometry (LC-ESI-HR-MS) and nuclear magnetic resonance (NMR) spectroscopy was proposed to determine the isotopic enrichment and structural integrity of deuterium labelled compounds. The proposed strategy involves recording full scan MS, extracting and integrating isotopic ions, and calculating the isotopic enrichment of the desired labelled compounds. NMR analysis confirms structural integrity or positions of labelled atoms and can provide insights into the relative percent isotopic purity. This strategy was used to evaluate the isotopic enrichment and structural integrity of in-house synthesized compounds as well as a series of commercially available deuterium labelled compounds. The % isotopic purity for labelled compounds of a benzofuranone derivative (BEN-d2), tamsulosin-d4 (TAM-d4), oxybutynin-d5 (OXY-d5), eplerenone-d3 (EPL-d3), and propafenone-d7 (PRO-d7) was calculated and found to be 94.7, 99.5, 98.8, 99.9, and 96.5, respectively. All the samples were run in triplicate and the results were observed to be reproducible.

A Prospective Study of Ultrasonographic and FNAC Correlation of Thyroid Swellings with Histopathology.

The present study was undertaken to identify the complimentary role of high resolution ultrasonography and fine needle aspiration cytology (FNAC) in diagnosis of thyroid gland swelling pathology, also determine sensitivity, specificity and accuracy of both USG and FNAC and correlate it with histopathology report. Total 75 cases of thyroid swellings were evaluated in detail by taking history, doing clinical examination, USG, FNAC and histopathology. USG findings were correlated with the FNAC report. After thyroidectomy surgery, USG and FNAC results were followed up and correlated with histopathology report. Thyroid swellings were more common in the age group of 31-40 years (34.66%) with female preponderance 70(93.33%). According to USG diagnosis, most common benign thyroid swelling was multinodular goitre (37.33). Amongst all the thyroid swellings, on FNAC, 17(18.67%) cases were diagnosed as a malignancy. 12(16%) cases were of follicular carcinoma which was the most common in this study. The sensitivity, specificity and diagnostic accuracy of USG was 86.66%, 91.66% and 90.66% respectively whereas sensitivity, specificity and diagnostic accuracy of FNAC was 93.3%, 95% and 94.66% respectively. USG and FNAC are simple methods of diagnosing thyroid gland swellings. The sensitivity, specificity and diagnostic accuracy of USG and FNAC for thyroid gland swellings was reasonably good. USG followed by FNAC increases the accuracy to diagnose various thyroid swellings so by which unnecessary thyroid gland surgery and hence complications can be avoided. However the most accurate and confirmatory diagnosis is given by histopathology.

Pathophysiology and Management of Neurogenic Pulmonary Edema in Patients with Acute Severe Brain Injury.

Acute brain injury (ABI) consists of any acquired insult to the brain and is a significant cause of morbidity and mortality worldwide. Approximately 20% to 30% of patients with ABI develop a lung injury called neurogenic pulmonary edema (NPE), and its development often results in poor outcomes. This article provides a narrative review of the evidence regarding proposed mechanisms of injury, diagnosis, and treatment of NPE in the critical care setting. PubMed and Ovid databases were searched for observational or prospective studies relevant to the diagnosis and treatment of NPE. Overall, studies showed that although the specific mechanisms responsible for NPE remain uncertain, putative mechanisms include vaso- and venoconstriction, catecholamine release with resultant pulmonary vasoconstriction called the "blast injury theory," increased vagal tone, and increased capillary permeability. Diagnosis involves identifying signs of pulmonary edema in patients who experienced a neurologic insult. Management strategies aim to address both brain and lung injury, and treatment modalities appear to work best when balanced toward maintaining a normal physiologic state. In summary, NPE is an often underdiagnosed but important sequela of ABI, which may result in additional long-term morbidity. It is therefore an important entity for providers to recognize and tailor their clinical approach toward.

A Study of Neuromyelitis Optica Spectrum Disorders (NMOSD): Disease Pattern Based on Antibody Status.

Introduction: Neuromyelitis optica (NMO) is a central demyelinating disorder, predominantly affecting the optic nerves and spinal cord and autoimmune basis. We aimed to analyze the clinical, laboratory, and imaging features associated with NMO spectrum disorders (NMOSD) according to the aquaporin 4 antibody (AQP4-Ab) serology status. Methods: The inclusion of the patients was based on the Wingerchuk criteria (2006) for NMO, known antibody status and has minimum 1-year follow-up. We analyzed and compared 46 patients with known antibody status. Results: AQP4-Ab positivity was 56.5%. The male to female ratio in the seropositive group was 1:7.7 and 1:1.2 in the seronegative group. The mean age of onset in seropositive patients was 36.8 years (vs 28.8 years in seronegative NMOSD patients). Clinical feature, cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) features were also different, but data from two subsets did not reach statistical significance. The relapse rate was higher in AQP4 positive NMOSD (84.6% vs 55% in the seronegative group). The recovery rate for AQP4 positive patients was poor (15%). Summary: We found differences in age, gender, and prognosis between the two groups. Antibody status may be a guiding factor in deciding the treatment approach during the first attack of NMOSD.

Negative Impact of Vestibular Suppressant Drugs on Provocative Positional Tests of BPPV: A Study from the Western Part of India.

AIMS: To study the impact of vestibular suppressant drugs (VSD) on provocative positional tests (PPT) in patients with benign paroxysmal positional vertigo (BPPV). SETTINGS AND DESIGN: A prospective case-control observational study. MATERIALS AND METHODS: Patients with a history suggestive of BPPV were tested for PPT. Patients with vertiginous symptoms and with nystagmus on PPT were classified as objective BPPV (O-BPPV, control group), while those without nystagmus with no alternate diagnosis were classified as subjective BPPV (S-BPPV, case group). Details of VSD treatment were noted in all the patients. In both groups, patients were instructed to discontinue VSD and were further assigned as the VSD and non-VSD subgroups. Patients were followed for 2 months with PPT every week. PPT positive patients were treated by vestibular rehabilitation maneuvers. STATISTICS: Student t-test with two-tailed, unpaired, was used for continuous scale and Chi-square test for categorical differences between the two groups. RESULTS: 295 consecutive BPPV patients were enrolled in the study, 55 in the S-BPPV group and 240 in the O-BPPV group. Significantly higher proportion of patients in the S-BPPV group were on VSD at presentation, 80.00% vs. 53.75% (OR 2.52; 95% CI: 1.30-4.86), P = 0.006. In an unadjusted analysis of the S-BPPV group following discontinuation of VSD, PPT became positive in 79.54% of patients as compared to 18.19% in the non-VSD group (OR 35.0; 95% CI: 6.2-197.3), P < 0.001. CONCLUSION: A higher proportion of S-BPPV patients were receiving VSD in comparison to O-BPPV at the initial visit. The PPT converted positive four times higher after ceasing the VSD in S-BPPV patients. STUDY DESIGN: Prospective case-control observational study.

Management of Cardiovascular Disease in Kidney Disease Study: Rationale and Design.

INTRODUCTION: Atherosclerosis, inflammation, and vascular stiffness are prominent interrelated risk factors contributing to the high incidence of cardiovascular disease (CVD) in patients with CKD. Conventional CVD management strategies in CKD largely target atherosclerotic CVD and have had a limited impact on the cardiovascular mortality in this population. Multiple in vivo and in vitro studies and epidemiological evidence from the rheumatologic cohorts have shown that low-dose hydroxychloroquine has beneficial effects on inflammation, endothelial function, insulin sensitivity, and metabolic syndrome. Our recent proof-of-concept animal study showed that hydroxychloroquine has marked protection against atherosclerosis and vascular stiffness. We hypothesize that hydroxychloroquine has the potential to provide significant cardiovascular benefits in patients with CKD. METHODS: The Management of Cardiovascular disease in Kidney disease study (NCT03636152) is a phase 2B, randomized, double-blind, placebo-controlled trial evaluating the effects of low-dose hydroxychloroquine therapy on the parameters of atherosclerosis, inflammation, and vascular stiffness in patients with CKD. The study plans to enroll 100 CKD patients estimated to be at high cardiovascular risk by a combination of low estimated glomerular filtration rate and albuminuria and treat them for 18 months with hydroxychloroquine or placebo in 1:1 allocation. RESULTS: The study will assess the change in the total carotid plaque volume as measured by serial noncontrast carotid MRI as the primary outcome and the serial changes in plasma inflammation markers, vascular stiffness, renal function, and the composition characteristics of the carotid plaque as secondary outcome measures. DISCUSSION/CONCLUSION: The results of this trial will provide the proof-of-applicability for hydroxychloroquine in the CVD in CKD. If positive, this trial should lead to phase-3 trials with clinical end points for this potentially transformative, novel, and inexpensive therapy for CVD in CKD.

Home run-results of a chronic kidney disease Telemedicine Patient Education Study.

BACKGROUND: Chronic kidney disease (CKD) incidence is increasing and associated mortality and morbidity are high. Educating patients is effective in delaying progression and establishing optimal renal replacement therapy (RRT). Tele-education/telemedicine (TM) can be an effective tool to provide such education, but there are no available data quantifying its effectiveness. We attempted to establish such evidence correlating the effect of education in patient choices and with the start of actual RRT. We present results from a 3-year pilot study evaluating the effectiveness of comprehensive predialysis education (CPE) through TM for CKD patients compared with a standard care group [face to face (FTF)]. The patient's ability to choose RRT was the primary endpoint. METHODS: This was a randomized controlled study providing CPE over three classes at nine sites (one FTF and eight TM). Three assessment tools were utilized to compare groups: CKD knowledge, literacy and quality of life. RESULTS: A total of 47.1% of FTF and 52.2% of TM patients reported not having enough information to choose a modality. This decreased by the third visit (FTF 7.4%, TM 13.2%). Home modality choices more than doubled in both groups (FTF 25.8-67.7%, TM 22.2-50.1%). In patients that completed one visit and needed to start RRT, 47% started on a home modality or received a pre-emptive transplant (home hemodialysis 6%, peritoneal dialysis 38%, transplant 3%). CONCLUSIONS: Results show almost 90% (TM 87%, FTF 95%) of the attendees could choose a modality after education. Home modality choices doubled. Patients were able to make an informed choice regardless of the modality of education.

Predictors of Ventricular Dysrhythmias in Neurology Intensive Care Unit Patients with Prolonged QTc.

INTRODUCTION: Acute neurological injury and several medications commonly administered in the Neuro ICU pose a risk of fatal cardiac dysrhythmias. The objective of this study is to identify the predictors of ventricular dysrhythmias in the Neuro ICU patients with prolonged QTc, thereby helping the clinicians make important treatment decisions. METHODS: We performed a retrospective review of all consecutive adults admitted to the Neuro ICU from January 2015 to September 2015 with a QTc interval ≥ 450 ms on electrocardiogram. RESULTS: A total of 170 patients with a mean age of 66 years (SD ± 16) were included in the final analysis. Eighty-seven patients (51%) were women. Median duration of hospitalization was 9 days (IQR 4-16). Most common primary diagnosis was ischemic stroke (38%) followed by cerebral hemorrhage (19%) and subarachnoid hemorrhage (8%). Mean QTc was 487 ms (SD ± 35, range 450-659 ms). There were 27 episodes (16%) of monomorphic non-sustained ventricular tachycardia and one episode of Torsades (1%). Three cardiac arrests (2%) were recorded, none resulting from ventricular dysrhythmias. In multivariate analysis, prolonged QTc ≥ 492 ms (p = 0.0008), supratentorial acute ischemic stroke (p = 0.005), prolonged hospitalization (p = 0.03), and premature ventricular complexes on ECG (p = 0.047) were all independently associated with increased risk of ventricular dysrhythmias. CONCLUSIONS: In this group of patients with prolonged QTc in the Neuro ICU, we observed several episodes of non-sustained ventricular tachycardia and identified important risk factors associated with their occurrence. This knowledge is essential to inform clinical decisions.

Autophagy Function and Regulation in Kidney Disease.

Autophagy is a dynamic process by which intracellular damaged macromolecules and organelles are degraded and recycled for the synthesis of new cellular components. Basal autophagy in the kidney acts as a quality control system and is vital for cellular metabolic and organelle homeostasis. Under pathological conditions, autophagy facilitates cellular adaptation; however, activation of autophagy in response to renal injury may be insufficient to provide protection, especially under dysregulated conditions. Kidney-specific deletion of Atg genes in mice has consistently demonstrated worsened acute kidney injury (AKI) outcomes supporting the notion of a pro-survival role of autophagy. Recent studies have also begun to unfold the role of autophagy in progressive renal disease and subsequent fibrosis. Autophagy also influences tubular cell death in renal injury. In this review, we reported the current understanding of autophagy regulation and its role in the pathogenesis of renal injury. In particular, the classic mammalian target of rapamycin (mTOR)-dependent signaling pathway and other mTOR-independent alternative signaling pathways of autophagy regulation were described. Finally, we summarized the impact of autophagy activation on different forms of cell death, including apoptosis and regulated necrosis, associated with the pathophysiology of renal injury. Understanding the regulatory mechanisms of autophagy would identify important targets for therapeutic approaches.

Relativistic coupling of phase and amplitude noise in optical interferometry.

Extraneous motion of optical elements in an interferometer leads to excess noise. Typically, fluctuations in the effective path length lead to phase noise, while beam pointing fluctuations lead to apparent amplitude noise. For a transmissive optic moving along the optical axis, neither effect should exist. However, relativity of motion suggests that, even in this case, small corrections of order v/c (v the velocity of the optic) give rise to phase and amplitude noise on the light. Here we calculate the effect of this relativistic mechanism of noise coupling and discuss when such an effect would limit the sensitivity of optical interferometers.

Long-term Adverse Events Associated With Acute Kidney Injury.

Acute kidney injury (AKI) occurs in approximately 10% to 15% of hospital-admitted patients and is associated with in-hospital mortality of 50% in patients requiring renal replacement therapy. Recently, multiple observational studies have demonstrated that patients who survive AKI have significant long-term consequences including cardiovascular events, progression to advanced-stage chronic kidney disease (CKD), and mortality. A direct link between AKI and CKD is provided by studies that demonstrate that some patients with normal renal function who develop AKI requiring dialysis never recover. In addition, in a large pediatric AKI population, 10% of the cohort developed CKD within 1 to 3 years. In a systemic review and meta-analysis in which 13 cohort studies were analyzed, patients with AKI had a hazard ratio (HR) of 8.8 for developing CKD, HR of 3.1 of developing end-stage kidney disease, and HR of 2.0 for mortality. AKI was also independently associated with risk for cardiovascular disease and congestive heart failure. These studies indicate that AKI is associated with important, long-term consequences and that AKI has become an important contributor to the end-stage kidney disease population. Prospective ongoing studies will better define the cause-effect relationship and delineate potential biomarkers that would identify AKI patients at risk for CKD, cardiovascular events, and mortality.

Effects of a Comprehensive Predialysis Education Program on the Home Dialysis Therapies: A Retrospective Cohort Study.

BACKGROUND: Improvement in the rates of home dialysis has been a desirable but difficult-to-achieve target for United States nephrology. Provision of comprehensive predialysis education (CPE) in institutes with established home dialysis programs has been shown to facilitate a higher home dialysis choice amongst chronic kidney disease (CKD) patients. Unfortunately, limited data have shown the efficacy of such programs in the United States or in institutes with small home dialysis (HoD) programs. METHODS: We report the retrospective findings examining the efficacy of a CPE program in the early period after its establishment, with reference to its impact on the choice and growth of a small HoD program. RESULTS: Over the initial 22 months since its inception, 108 patients were enrolled in the CPE clinic. Seventy percent of patients receiving CPE chose HoD, of which 55% chose peritoneal dialysis (PD) and 15% chose home hemodialysis (HHD). Rates of HoD choice were similar across the spectrum of socio-economic variables. Of just over half (54.6%) of those choosing to return for more than 1 session, 25.3%, changed their modality preference after the first education session, and nearly all reached a final modality selection by the end of the third visit. Initiation of the CPE program resulted in a 216% growth in HoD census over the same period and resulted in near doubling of HoD prevalence to 38% of all dialysis patients. CONCLUSIONS: Comprehensive patient education improves the choice and prevalence of HoD therapies. We further find that 3 sessions of CPE may provide needed resources for the large majority of subjects for adequate decision-making.

Carbamylated Low-Density Lipoprotein (cLDL)-Mediated Induction of Autophagy and Its Role in Endothelial Cell Injury.

Patients with chronic kidney disease (CKD) have high risk of cardiovascular complications. Plasma levels of carbamylated proteins produced by urea-derived isocyanate or thiocyanate are elevated in CKD patients and that they are significant predictors of cardiovascular events and all-cause mortality. Carbamylated LDL (cLDL) has pro-atherogenic properties and is known to affect major biological processes relevant to atherosclerosis including endothelial cell injury. The underlying mechanisms of cLDL-induced endothelial cell injury are not well understood. Although autophagy has been implicated in atherosclerosis, cLDL-mediated induction of autophagy and its role in endothelial cell injury is unknown. Our studies demonstrate that human coronary artery endothelial cells (HCAECs) respond to cLDL by specific induction of key autophagy proteins including LC3-I, beclin-1, Atg5, formation of lipid-conjugated LC3-II protein, and formation of punctate dots of autophagosome-associated LC3-II. We demonstrated that autophagy induction is an immediate response to cLDL and occurred in a dose and time-dependent manner. Inhibition of cLDL-induced autophagy by a specific siRNA to LC3 as well as by an autophagy inhibitor provided protection from cLDL-induced cell death and DNA fragmentation. Our studies demonstrate that autophagy plays an important role in cLDL-mediated endothelial cell injury and may provide one of the underlying mechanisms for the pathogenesis of cLDL-induced atherosclerosis in CKD patients.

Combined Central and Peripheral Demyelination.

Demyelinating disorders are very common, but remains isolated to the part of nervous system they involve. However, infrequently, combined involvement of central and peripheral nervous system with demyelinating process have been described. We report one such rare case, with possible theories of common etiological basis. We present a middle aged male patient with Chronic Inflammatory Demyelinating Polyneuropathy(CIDP), who responded to immuno-modulation. Subsequently, he developed Acute Transverse Myelitis (ATM). Recently a common substrate protein, NF186 has been described as responsible for this rare clinical entity.