Study of Glycemic Variability in Well-controlled Type 2 Diabetic Patients Using Continuous Glucose Monitoring System.

INTRODUCTION: The world has changed tremendously for patients suffering from diabetes mellitus with the development of cutting-edge technologies like continuous glucose monitoring and flash glucose monitoring systems. Now, the details of constant fluctuations of glucose in their blood can be monitored not only by medical professionals but also by patients, and this is called glycemic variability (GV). Traditional metrics of glycemic control measurement, such as glycated hemoglobin (HbA1c), fail to reflect various short-term glycemic changes like postprandial hyperglycemia and hypoglycemic episodes, paving the way to the occurrence of various diabetic complications even in asymptomatic, well-controlled diabetic patients. This need for advanced management of diabetes and effective monitoring of these swings in blood glucose can be met by using a continuous glucose monitoring system (CGMS). AIM AND OBJECTIVE: To evaluate the extent of GV in well-controlled type 2 diabetes mellitus (T2DM) patients using a flash CGMS and to assess the correlation between GV and HbA1c. MATERIALS AND METHODS: A hospital-based prospective observational study was carried out from May 2020 to Oct 2021 at the Department of Medicine, SMS Hospital, Jaipur, Rajasthan (India), after approval from the Ethics Committee of the institution. A total of 30 patients with well-controlled T2DM (HbA1c was ≥6.5, but ≤7.5) were included in the study using simple random techniques after written informed consent from patients. Patients were studied for glycemic excursions over a period of 7 days by using FreeStyle® Libre Pro™, which is a flash glucose monitoring system. The CGM sensor was attached to the left upper arm of the patient on day 0 and removed on day 7. The data recorded in the sensor was then retrieved using pre-installed computer software and analyzed using standard CGM metrics like standard deviation (SD), percentage coefficient of variation (%CV), time above range (TAR), time below range (TBR), and time in range (TIR), out of which %CV was used to quantify GV. %CV has been used to cluster patients into four cohorts from best to worst, namely: best/low CV ≤ 10%, intermediate CV from 10 to 20%, high CV from 20 to 30%, and very high CV of >30%. Scatterplots are used to establish correlations between various parameters. RESULT: Data from a total of 30 patients were analyzed using CGMS and thus used for calculating standard CGM metrics; glucose readings every 15 minutes were recorded consecutively for 7-day periods, making it a total of 672 readings for each patient. Interpreting the CGM data of all 30 patients, the following results were found: the mean blood glucose of all cases is 134.925 ± 22.323 mg/dL, the mean SD of blood glucose of all cases is 35.348 ± 9.388 mg/dL, the mean of %CV of all cases is 26.376 ± 6.193%. CGM parameters of time are used in the form of percentages, and the following results were found: the mean of TAR, TBR, and TIR is 14.425 ± 13.211, 5.771 ± 6.808, and 82.594 ± 12.888%, respectively. Clustering the patients into cohorts, the proportion of patients exhibiting best/low %CV (10%) is 0, intermediate %CV (10-20%) is 16.67% (five out of 30 patients), high %CV (20-30%) is 50% (15 out of 30 patients) and very high %CV (>30%) is 33.33% (10 out of 30 patients). Also, there is no significant correlation found between HbA1c and %CV (ρ = 0.076, p-value = 0.690); a significant negative correlation was found between %CV and TIR (ρ = -0.604, p < 0.001S); a positive correlation of %CV with TAR and TBR is significant (ρ = 0.816, p-value of <0.001). CONCLUSION: Using a flash CGMS device and considering %CV as the parameter and primary measure of GV, the study demonstrated the overall instability of a person's glycemic control, making note of unrecognized events of hypoglycemia and hyperglycemia in asymptomatic well-controlled T2DM patients, revealing the overall volatile glycemic control. The most important finding of this study is that even those diabetics who are considered well-controlled experience a great degree of GV as assessed by CGM-derived metrics. This study also demonstrated that there is no significant correlation between HbA1c and GV, suggesting that patients may not have optimal control of their diabetes despite having "normal HbA1c" values; hence, GV can be considered an HbA1c-independent danger factor, having more harmful effects than sustained hyperglycemia in the growth of diabetic complications. So, by using CGM-derived metrics, the measurement of GV has the potential to complement HbA1c data. In this manner, a more comprehensive assessment of glycemic excursions can be provided for better treatment decisions, thereby facilitating optimal glycemic control, which is essential for reducing overall complications and promoting good quality of life.

A Study of Relationships between the HbA1c Level and Inflammatory Markers, Neutrophil-to-Lymphocyte Ratio, and Monocyte-to-Lymphocyte Ratio in Controlled and Uncontrolled Type 2 Diabetes Mellitus.

AIM AND OBJECTIVE: To assess the relationship between glycated hemoglobin (HbA1c) with inflammatory markers, neutrophil-to-lymphocytes ratio (NLR), and monocyte-to-lymphocytes ratio (MLR) in controlled and uncontrolled type 2 diabetes patients. MATERIALS AND METHODS: This was a hospital-based cross-sectional study conducted at the Department of Medicine, SMS Hospital, and an attached group of hospitals (Jaipur, Rajasthan, India) after informed consent from the Ethics Committee of the institute. After obtaining informed consent from patients who met the inclusion and exclusion criteria, 200 diabetic patients were included in the study using the simple randomization method. Following a detailed history and diagnosis, vital demographic information, and blood tests were collected from patients via a predesigned preliminary questionnaire. The following blood tests were collected: white blood cell (WBC), Hb, hematocrit (HCT), red cell distribution width (RDW), neutrophils, lymphocytes, HbA1c, blood glucose, NLR ratio, and MLR ratio. Data were entered and analyzed using Statistical Package for the Social Sciences version 22. RESULTS: The mean age of patients with controlled diabetes mellitus was 54.10 years, while that of patients with uncontrolled diabetes mellitus was 55.3 years. Glycemic control was more in the age group of 51-60 years. Around 54% of males and 46% of females were included in the present study, and no association was found between the two genders with poor and good glycemic control. Around 63.29% of participants with uncontrolled diabetes have an increased NLR, and 61.39% of participants with uncontrolled diabetes have an increased MLR. A strong association was found between the NLR and MLR with the glycemic control. CONCLUSION: Uncontrolled diabetes mellitus had a positive association with inflammatory markers, that is, NLR and MLR. STATEMENT OF SIGNIFICANCE: Diabetes mellitus is the most common metabolic disorder in Asian countries. It leads to many acute and chronic complications in uncontrolled diabetes. Markers like the NLR ratio and MLR ratio are inexpensive and easily available for blood investigation. Hence, these markers are quite useful in differentiating controlled and uncontrolled diabetes and, therefore, useful in predicting blood sugar control in type 2 diabetes mellitus.

Nickel-Catalyzed Tandem Cyclization of 1,6-Diynes with Indolines/Indoles through Dual C-H Bond Activation.

A nickel-catalyzed site-selective tandem cyclization of 1,6-diynes with substituted indolines or indoles through consecutive dual C-H bond activation is described. In the reaction, substituted fused indole and carbazole derivatives were observed in good to excellent yields, in which three consecutive C-C bonds formed in one pot. Later, in the presence of DDQ, the aromatization of the indoline derivative was converted to the indole derivative. A possible reaction mechanism involving dual C-H bond activation as a key step was proposed to account for the present reaction.

XRCC3 and NBS1 gene polymorphisms modulate the risk of pre-oral cancer and oral cancer in the North Indian population.

Background: Oral cancer is alarming disease in the developing countries like India. DNA repair capacity may affect by genetic polymorphisms in DNA repair genes and thus may cause to cancer. XRCC3 involves in homologous recombination repair pathway and repair DNA damage and crosslinks while, NBS1 participate in repair of double strand DNA break and starts the cell-cycle checkpoint signaling. Aims and Objectives: This study was to conducted to find the association of XRCC3, NBS1 polymorphisms with oral disease. Results: TT genotype of XRCC3 was associated with high risk of precancerous lesions and oral cancerous lesions (P value=0.0001, OR=9.68, 95% CI=2.82-33.21; and P value=0.0001, OR=13.10, 95% CI=3.38-50.73 respectively). We did not observe any interactions of XRCC3 polymorphism with demographic parameters in influencing the risk of oral diseases. Variant allele genotypes (CG, GG) of NBS1 (C>G) polymorphism showed protective association with Oral submucous fibrosis (OSMF), lichen planus as well as oral cancer (OR=0.31, OR=0.01; OR=0.39, OR=0.03; OR=0.43, OR=0.31 respectively). Particularly, tobacco chewer with CG & GG genotypes were at decrease risk of oral diseases (P value=0.02, OR=0.32, 95% CI=0.12-0.80). Compared to CC/CC combined genotype CG/CC, CG/CT, GG/CC and CG/CT genotypes decreased the risk of oral disease (OR=0.05, 0.47, 0.26 & 0.14 respectively). Conclusion: This study concludes that SNP in XRCC3, NBS1 affects susceptibility to oral disease.

The Taq 1 polymorphism of Vitamin D receptor gene is associated with oral cancer and preoral cancer in North Indian population.

Background: Oral cancer is known as one of the most common cancers, with a poor prognosis, related to delayed clinical diagnosis, either due to the lack of particular biomarkers related to the disease or costly therapeutic alternatives. Aims and Objectives: In this study association of single nucleotide polymorphism (Taq1, T>C) in Vitamin D receptor gene with oral cancer and pre oral cancer was studied. Materials and Methods: Total 230 patients of precancerous oral lesions (Leukoplakia 70, Oral Sub mucous fibrosis 90, Lichen Planus 70), 72 oral cancer patients and 300 healthy control subjects were genotyped by PCR-RFLP methods. Chi-square test was used for calculation of genotype and allele frequencies. Results: Mutant genotype CC as well as C allele were found to significantly decrease the risk of oral disease (P value=0.04, OR=0.60 and P value=0.02, OR=0.75 respectively). In particular, compared to non smokers, smokers with TC & CC genotypes were at decrease risk of oral diseases (P value=0.0001, OR=0.04). The mutant allele genotype CC as well as the mutant allele C showed protective association with leukoplakia (P value=0.01, OR=0.39 & P value=0.009, OR=0.59 respectively). However, individual with CC genotype had developed high cell differentiated grade at diagnosis (OR= 3.78, P value= 0.008). Conclusions: This study concludes that VDR (Taq1) polymorphism is associated with oral cancer and pre oral cancer susceptibility in North Indian population.

Cobalt(III)-Catalyzed Regioselective [4 + 2]-Annulation of N-Chlorobenzamides with Substituted Alkenes.

A Co(III)-catalyzed redox-neutral [4 + 2] annulation of N-chlorobenzamides/acrylamides with substituted alkenes at ambient temperature is demonstrated. Using this protocol, pharmaceutically important 3,4-dihydroisoquinolinone derivatives were synthesized in good yields. Intriguingly, the synthetically useful functional group of allylic coupling partners such as sulfonyl, carbonate, acetate, phosphate, amide, nitrile, and silane were retained in the final cyclized product. The present annulation reaction was compatible with various substituted benzamides and allylic coupling partners. To support the proposed reaction mechanism, competition experiments, deuterium labeling studies, and kinetic isotope effect studies were performed.

A Case Series on Neuropathogenic Nature of an Ancient Disease ----Tuberculosis.

Tuberculosis is one of the oldest diseases known to affect humans and the top cause of infectious death worldwide caused by M. tuberculosis complex. Tuberculosis may be pulmonary, extra-pulmonary or both. Nervous system tuberculosis is relatively rare and has protean nature of symptoms so poses diagnostic difficulty. Neurological manifestations of tuberculosis includes 1) intracranial 2) spinal 3) peripheral nerve tuberculosis. Central nervous system tuberculosis accounts about 5% of extra pulmonary cases and 1% all tuberculosis. MATERIAL: Here we are presenting the series of 10 cases which have wide variety of neuropathogenic nature of tuberculosis. OBSERVATION: Here we are presenting the series of 10 cases which have wide variety of neuropathogenic nature of tuberculosis. These includes 1) Tubercular cortical vein thrombosis -patient who is a known case of pulmonary tuberculosis presented with severe headache, seizure and altered behavior, MRI brain shows cortical vein thrombosis and normal coagulation profile (Review of literature shows only 4 cases). 2)Tubercular myelitis/ arachnoiditis-presented with low backache and bilateral lower limb weakness,CSF panel and MRI L S spine shows tubercular arachnoiditis/myelitis. 3)Tubercular peripheral neuropathy; patient who is a non- diabetic presented with pain abdomen and bilateral lower limb tingling and numbness with no past history of treatment with anti-tubercular drug, CECT abdomen shows ileocecal tuberculosis and NCS study shows sensory affection of lower limb nerve. 4)Tuberculoma-patient presented with severe headache, seizure and altered behavior, MRI brain shows tuberculoma. 5) and 6) are tubercular vascular infarct in 1 of these 2 cases patient was having multiple necrotic foci and few foci of cavitation in left hilar region which is extending into left inferior pulmonary vein and even reaching upto left atrium. 7) and 8) cases are pott's spine who presented with low backache. 9) and 10) are tubercular meningitis and tubercular meningitis with hydrocephalus respectively. These patients were treated according to their diagnosis and for focal neurological deficit physiotherapy was advised. Except a case of septic foci emboli from left atrium which shows moderate recovery rest all cases shows good recovery at discharge. CONCLUSION: There is paucity of literature on neuropathogenic nature of tuberculosis. In this case series we are presenting the series of 10 cases of tubercular nervous system manifestations so that it will helps to diagnose the disease as early as possible and allows us to initiate the prompt treatment so that we can mitigate the significant morbidity and mortality among survivors of nervous system tubercular disease.

Cobalt(III)-Catalyzed Chemo- and Regioselective [4 + 2]-Annulation of Aromatic Sulfoxonium Ylides with 1,3-Diynes.

Air-stable, highly abundant, and cost-effective Co(III)-catalyzed redox-neutral [4 + 2]-annulation of aromatic sulfoxonium ylides with 1,3-diynes providing useful substituted 1-naphthol derivatives in a regioselective manner is described. Further, the prepared 1-naphthols having internal alkyne were converted into useful polycarbocyclic molecules and spiro-dienone derivatives in good-to-excellent yields. A possible reaction mechanism involving ortho C-H activation as a key step was proposed and supported by deuterium labeling and kinetic isotope labeling studies.

Risk Modulation of Oral Pre Cancer and Cancer with Polymorphisms in XPD and XPG Genes in North Indian Population.

Background: Environmental carcinogens cause DNA damages which if not repaired properly, may increase the risk of cancer. The Xerodermapigmentosum group D (XPD) and group G (XPG) genes are essential genes for DNA repair and alteration in DNA repair causes cancer. The present study aimed to evaluate the relationship between XPD and XPG polymorphisms and risk of oral pre cancer and cancer. Methods: Present study genotyped 302 samples of oral diseases and 300 controls for XPD (A/C) and XPG (G/C) polymorphisms with PCR-RFLP method. Results: Our result showed that compared to AA genotype frequency of AC and CC genotype for XPD(A/C) polymorphism were significantly lower among cases than in control and are associated with decreased risk of oral diseases (OR= 0.621 and 0.603 respectively). In contrast with reference to GG genotype the frequency of CC genotype of XPG (G/C) was significantly higher in case than in control population (p value=0.004) and found to increase the risk of oral diseases (OR= 2.077). Particularly C allele for XPD A/C polymorphism was found to be associated with decreased risk of Lichen planus and increased risk of ( OR = 0.470 and 1.541 respectively) oral cancer. While C allele of XPG G/C polymorphism significantly increased the risk of Oral Submucous Fibrosis and Leukoplakia (OR= 1.879 and 1.837 respectively) but not of Lichen planus and oral cancer. In combined genotype analysis from the aforesaid polymorphisms presence of C allele for XPD (A/C) polymorphisms were found to decrease the risk of oral diseases. However, the same C allele was observed to increase the chance of having high stage disease (OR= 5.71) with nodal involvement (OR= 6.78) once the cancer been initiated. Conclusion: This work shows association of XPD (A/C), XPG (G/C) polymorphisms with the development of pre oral cancer as well as oral cancer and its clinical courses.

Modulation of risk of squamous cell carcinoma head and neck in North Indian population with polymorphisms in xeroderma pigmentosum complementation Group C gene.

BACKGROUND: Genetic variations in nucleotide excision repair genes can alter the risk of squamous cell carcinoma of head and neck (SCCHN). MATERIALS AND METHODS: The present study has genotyped 334 subjects from North Indian population for xeroderma pigmentosum complementation Group C (XPC) rs2228001A>C, XPC rs77907221 polyadenylate (PAT) deletion/insertion (D/I), xeroderma pigmentosum complementation Group D - rs13181A>C, and xeroderma pigmentosum complementation Type G rs17655 G>C polymorphisms with polymerase chain reaction (PCR)-restriction-fragment length polymorphism or allele-specific PCR methods. RESULTS: Compared to D allele, I allele for XPC PAT D/I polymorphism was associated with significantly decreased the risk of SCCHN (odds ratios = 0.67, 95% confidence interval [CI] =0.48-0.94, P = 0.03). Haplotype CI constituted from XPC polymorphisms was also associated with decreased risk of SCCHN (P = 0.004). In contrast, haplotype Crohn's disease significantly increased the risk for SCCHN (P < 0.00). A significant early onset of SCCHN was observed in individuals with CC genotype for XPC A>C polymorphism (P = 0.004). CONCLUSION: Our results suggest a possible risk modulation for SCCHN with XPC polymorphisms in North Indian population.