Determination of Factors Associated with Upstage in Atypical Ductal Hyperplasia to Identify Low-Risk Patients Where Active Surveillance May be an Alternative.

BACKGROUND: Excision is routinely recommended for atypical ductal hyperplasia (ADH) found on core biopsy given cancer upstage rates of near 20%. Identifying a cohort at low-risk for upstage may avoid low-value surgery. Objectives were to elucidate factors predictive of upstage in ADH, specifically near-complete core sampling, to potentially define a group at low upstage risk. PATIENTS AND METHODS: This retrospective, cross-sectional, multi-institutional study from 2015 to 2019 of 221 ADH lesions in 216 patients who underwent excision or active observation (≥ 12 months imaging surveillance, mean follow-up 32.6 months) evaluated clinical, radiologic, pathologic, and procedural factors for association with upstage. Radiologists prospectively examined imaging for lesional size and sampling proportion. RESULTS: Upstage occurred in 37 (16.7%) lesions, 25 (67.6%) to ductal carcinoma in situ (DCIS) and 12 (32.4%) to invasive cancer. Factors independently predictive of upstage were lesion size ≥ 10 mm (OR 5.47, 95% CI 2.03-14.77, p < 0.001), pathologic suspicion for DCIS (OR 12.29, 95% CI 3.24-46.56, p < 0.001), and calcification distribution pattern (OR 8.08, 95% CI 2.04-32.00, p = 0.003, "regional"; OR 19.28, 95% CI 3.47-106.97, p < 0.001, "linear"). Near-complete sampling was not correlated with upstage (p = 0.64). All three significant predictors were absent in 65 (29.4%) cases, with a 1.5% upstage rate. CONCLUSIONS: The upstage rate among 221 ADH lesions was 16.7%, highest in lesions ≥ 10 mm, with pathologic suspicion of DCIS, and linear/regional calcifications on mammography. Conversely, 30% of the cohort exhibited all low-risk factors, with an upstage rate < 2%, suggesting that active surveillance may be permissible in lieu of surgery.

Evaluation of Immature Granulocyte Count as the Earliest Biomarker for Sepsis.

Background: Diagnosing sepsis early is important for its successful management. Various biomarkers are being used currently, but mostly they are either expensive or not readily available. This study aims to evaluate usefulness of automated immature granulocyte count (IG#) and immature granulocyte percentage (IG%) as early diagnostic markers of sepsis and compares it to other established predictive markers. Patients and methods: In this prospective observational study, 137 eligible, critically ill, nonseptic intensive care unit patients were analyzed for automated IG#, IG%, serum procalcitonin (PCT), and blood lactate (Lac), daily for 7 days after recruitment. Patients were followed for the development of sepsis, defined by the new Sepsis-3 criteria. The study was divided into four time periods of 24 hours each with respect to the day of developing organ dysfunction. Using area under receiver operator characteristic and diagnostic odds ratio (DOR) methods, the best biomarker for the prediction of sepsis in each time period was calculated. Results: IG# and IG% were the earliest biomarkers to have a significant discriminating value with area under the curve of 0.81 and 0.82, respectively, as early as 24 hours before clinical sepsis is diagnosed by Sepsis-3 criteria. Both IG# and IG% have a high DOR of 34.91 and 18.11, respectively, when compared to others like PCT and Lac having a DOR of 27.06 and 4.78, respectively. Conclusion: IG# and IG% are easily available, rapid, and inexpensive tools to differentiate between septic and nonseptic patients with high specificity and sensitivity. It is the earliest biomarker to show a significant rise in patients developing sepsis. How to cite this article: Bhansaly P, Mehta S, Sharma N, Gupta E, Mehta S, Gupta S. Evaluation of Immature Granulocyte Count as the Earliest Biomarker for Sepsis. Indian J Crit Care Med 2022;26(2):216-223.

Differential ETS1 binding to T:G mismatches within a CpG dinucleotide contributes to C-to-T somatic mutation rate of the IDH2 hotspot at codon Arg140.

Cytosine to thymine (C>T) somatic mutation is highly enriched in certain types of cancer, and most commonly occurs via deamination of a 5-methylcytosine (5mC) to thymine, in the context of a CpG dinucleotide. In theory, deamination should occur at equal rates to both 5mC nucleotides on opposite strands. In most cases, the resulting T:G or G:T mismatch can be repaired by thymine DNA glycosylase activities. However, while some hotspot-associated CpG mutations have approximately equal numbers of mutations that resulted either from C>T or G>A in a CpG dinucleotide, many showed strand bias, being skewed toward C>T of the first base pair or G>A of the second base pair. Using the IDH2 Arg140 codon as a case study, we show that the two possible T:G mismatches at the codon-specific CpG site have differing effects on transcription factor ETS1 binding affinity, differentially affecting access of a repair enzyme (MBD4) to the deamination-caused T:G mismatch. Our study thus provides a plausible mechanism for exclusion of repair enzymes by the differential binding of transcription factors affecting the rate at which the antecedent opposite-strand mutations occur.

Quantitative Analysis of Contrast-enhanced Mammography for Risk Stratification of Benign Versus Malignant Disease and Molecular Subtype.

OBJECTIVE: To assess quantitative enhancement of benign, high-risk, and malignant lesions and differences in molecular subtype and grade of malignant lesions on contrast-enhanced mammography (CEM). METHODS: This IRB-approved retrospective study included women who underwent CEM for diagnostic work-up of a breast lesion between 2014 and 2020. Inclusion criteria were women who had diagnostic work-up with CEM and had BI-RADS 1 or 2 with one year follow-up, BI-RADS 3 with tissue diagnosis or stability for 2 years, or BI-RADS 4 or 5 with tissue diagnosis. An enhancement ratio was calculated for all lesions. This was obtained by drawing a region of interest within the lesion and a second region of interest in the nonenhancing background tissue using a program developed with MATLAB. Descriptive statistics were evaluated using chi-squared tests, Fisher exact tests, and analysis of variance. A logistic regression model was used to predict cancer outcome using the enhancement ratio. Statistical significance was defined as P < 0.05. RESULTS: There were 332 lesions in 210 women that met study criteria. Of the 332 lesions, 50.9% (169/332) were malignant, 5.7% (19/332) were high-risk, and 43.4% (144/332) were benign. Enhancement intensity of malignant lesions was higher than benign lesions. Odds ratio for quantitative enhancement of malignant lesions was 30.15 (P < 0.0001). Enhancement ratio above 1.49 had an 84.0% sensitivity and 84.0% specificity for malignancy. HER2-enriched breast cancers had significantly higher mean enhancement ratios (P = 0.0062). CONCLUSION: Quantitative enhancement on CEM demonstrated that malignant breast lesions had higher mean enhancement intensity than benign lesions.

The inactive Dnmt3b3 isoform preferentially enhances Dnmt3b-mediated DNA methylation.

The de novo DNA methyltransferases Dnmt3a and Dnmt3b play crucial roles in developmental and cellular processes. Their enzymatic activities are stimulated by a regulatory protein Dnmt3L (Dnmt3-like) in vitro. However, genetic evidence indicates that Dnmt3L functions predominantly as a regulator of Dnmt3a in germ cells. How Dnmt3a and Dnmt3b activities are regulated during embryonic development and in somatic cells remains largely unknown. Here we show that Dnmt3b3, a catalytically inactive Dnmt3b isoform expressed in differentiated cells, positively regulates de novo methylation by Dnmt3a and Dnmt3b with a preference for Dnmt3b. Dnmt3b3 is equally potent as Dnmt3L in stimulating the activities of Dnmt3a2 and Dnmt3b2 in vitro. Like Dnmt3L, Dnmt3b3 forms a complex with Dnmt3a2 with a stoichiometry of 2:2. However, rescue experiments in Dnmt3a/3b/3l triple-knockout (TKO) mouse embryonic stem cells (mESCs) reveal that Dnmt3b3 prefers Dnmt3b2 over Dnmt3a2 in remethylating genomic sequences. Dnmt3a2, an active isoform that lacks the N-terminal uncharacterized region of Dnmt3a1 including a nuclear localization signal, has very low activity in TKO mESCs, indicating that an accessory protein is absolutely required for its function. Our results suggest that Dnmt3b3 and perhaps similar Dnmt3b isoforms facilitate de novo DNA methylation during embryonic development and in somatic cells.

Rheumatology in Malaysia.

Malaysia is a developing country in the South-East Asian region with a significant burden of disability from musculoskeletal disease. Rheumatology in Malaysia is a relatively young speciality. Currently, there is approximately 1 rheumatologist per 390,000 population, mostly concentrated in the urban areas. This article aims to give a brief overview of the research in rheumatology, the healthcare system, and rheumatology training and education in Malaysia. From 1950 until mid-2019, there were 547 publications about rheumatological conditions from Malaysia, with a 27-fold increase in the numbers from the period before 1980 compared to 2010-2019. Although there is universal access to healthcare through the public (government funded) hospitals and clinics, as well as a system of private healthcare, funding for expensive biological therapies remain patchy and scarce, leading to significant under-utilization of such treatments in rheumatology patients. Training in rheumatology in Malaysia is well established with a formalised training curriculum introduced in 2004, followed by the introduction of training in musculoskeletal ultrasound in 2006. To improve care for patients with musculoskeletal conditions, there has been regular continuing educational meetings and courses, not just for rheumatologists, but also for other medical professionals, as not all areas in Malaysia have easy access to rheumatology services. Thus overall, despite the small number of rheumatologists, rheumatology in Malaysia has made encouraging progress over the past 2 decades, but improvements in patient care, training, education and research need to continue in the future.

Rheumatological publications from Malaysia: a bibliometric study.

OBJECTIVES: To assess the content, authorship and study design of rheumatological publications written by Malaysian authors or about rheumatological conditions in Malaysia. METHODS: The Malaysian Medical Repository (MyMedR), a web-based database of Malaysian health and medical publications, and Scopus were searched to retrieve rheumatological publications from Malaysia, for the period 1950 until 30 June 2019. The type and number of publications in each rheumatological subject area and the overall trend of publication numbers and citations were analysed. RESULTS: 547 publications were found for the time period studied. There was a 27-fold increase in the number of publications from the period up to 1980 compared to 2010-2019. The median number of citations per paper was 5, but unlike the number of publications, there was only a slight increase in the number of citations with time. 84.5% of the papers were cited at least once. The top 3 conditions generating the most publications were systemic lupus erythematosus, 36.7%, followed by rheumatoid arthritis, 17.0%, and osteoporosis, 13.9%. CONCLUSIONS: The number of rheumatological publications in Malaysia have increased over time, especially in the last decade. However, the average number of citations per publications remains low and the majority of publications are in journals with low impact factors. Thus, the quality of rheumatological publications from Malaysia can be further improved.Key Points• There have been only a limited number of bibliometric analysis of rheumatology publications from Asia.• In Malaysia, the number of rheumatology publications has increased over time.• However, there is still room for improvement in terms of the quality of the publications.

Clinical significance of SLC2A9/GLUT9 rs11722228 polymorphisms in gout.

AIM: The main objective of this study is to elucidate the clinical significance of the SLC2A9/GLUT9 rs11722228 polymorphism among male gout patients. METHOD: We consecutively recruited all newly diagnosed male gout patients who were treatment-naive from the rheumatology outpatient clinics of two Malaysian hospitals. Age-matched healthy male adults were employed as controls. All subjects were tested for the SLC2A9/GLUT9 rs11722228 genotypes, serum uric acid (SUA), urine uric acid and creatinine levels. All gout subjects were examined for the presence of tophi and sonographically screened for renal calculi. RESULTS: A total of 73 male gout patients and 73 age-matched healthy male adults were recruited in this study. The genotypic frequencies of SLC2A9/GLUT9 rs1172228 did not differ significantly between the gout cases and the healthy controls. The gout subjects with the CC genotype had significantly higher SUA levels (P = 0.002), family history of gout (P < 0.050) and the occurrence of renal calculi (P = 0.026). The SUA-adjusted odds ratios (OR) of the occurrence of renal calculi in the CC genotype (OR = 1 [reference]) was significantly higher than the CT genotype (OR = 0.338, 95%CI: 0.141-0.813) and the TT genotype (OR = 0.271, 95%CI: 0.086-0.854). CONCLUSIONS: The genotypic distribution of SLC2A9/GLUT9 rs1172228 in male gout patients did not differ significantly from that of healthy male controls. However, the CC genotype in gout had significant associations with higher levels of SUA, renal calculi and a positive family history of gout.

Effects of 25-hydroxyvitamin D and vitamin D-binding protein on bone mineral density and disease activity in Malaysian patients with rheumatoid arthritis.

AIM: Vitamin D3 [25(OH)D] has been shown to be important in bone health and can influence rheumatoid arthritis (RA) disease activity. Vitamin D-binding protein (VDBP) levels vary with race and may modulate 'bioavailable' levels of 25(OH)D. The aim of this study was to explore the relationships between 25(OH)D, VDBP and clinical factors on bone mineral density (BMD) in a group of multi-ethnic Malaysian RA patients and healthy controls. METHODS: A cross-sectional study of 77 female RA patients and 29 controls was performed. Serum 25(OH)D was measured using the Elecsys® Vitamin D total assay. Serum VDBP was measured using a Quantikine® enzyme-linked immunosorbent assay kit. BMD was assessed using dual-energy X-ray absorptiometry (DXA). RESULTS: Overall, mean 25(OH)D levels were 42.66 ± 21.75 nmol/L with no significant difference between RA patients and controls. 25(OH)D levels were significantly higher in Chinese, compared to Malay/Indian subjects. In RA patients, menopausal status and body mass index (BMI) were significantly associated with BMD but not 25(OH)D or RA Disease Activity Score of 28 joints (DAS28). There was no significant correlation between 25(OH)D and DAS28, even after correction for menopausal status and BMI. VDBP levels were not significantly different between the races and did not significantly correlate with BMD, 25(OH)D overall, or DAS28 in RA patients. CONCLUSIONS: In Malaysian RA patients, menopausal status and BMI were more important influences on BMD than 25(OH)D or RA disease activity. The utility of measuring VDBP levels in this population remains uncertain.

Correction: Correlation of serum cartilage oligometric matrix protein (COMP) and interleukin-16 (IL-16) levels with disease severity in primary knee osteoarthritis: A pilot study in a Malaysian population.

[This corrects the article DOI: 10.1371/journal.pone.0184802.].

Correlation of serum cartilage oligomeric matrix protein (COMP) and interleukin-16 (IL-16) levels with disease severity in primary knee osteoarthritis: A pilot study in a Malaysian population.

OBJECTIVE: The aim of this study was to investigate the correlations between serum cartilage oligomeric matrix protein (COMP), interleukin-16 (IL-16) and different grades of knee osteoarthritis (KOA) in Malaysian subjects. METHODS: Ninety subjects were recruited comprising 30 with Kellgren-Lawrence (K-L) grade 2 KOA, 27 with K-L grade 3 KOA, 7 with grade 4 KOA, and 30 healthy controls. All subjects completed the Western Ontario and McMaster Universities Arthritis Index (WOMAC) questionnaire. Serum COMP and IL-16 levels were measured using ELISA and their values log transformed to ensure a normal distribution. RESULTS: There was no significant differences in levels of log serum COMP and IL-16 between healthy controls and KOA patients. There were no significant differences in the log serum COMP and IL-16 levels within the different K-L grades in the KOA patients. In KOA patients, log serum IL-16 levels significantly correlated with the WOMAC score (p = 0.001) and its subscales, pain (p = 0.005), stiffness (p = 0.019) and physical function (p<0.0001). Serum IL-16 levels were significantly higher in Malaysian Indians compared to Malays and Chinese (p = 0.024). CONCLUSIONS: In this multi-ethnic Malaysian population, there was no difference in serum COMP and IL-16 levels between healthy controls and patients with KOA, nor was there any difference in serum COMP or IL-16 levels across the various K-L grades of KOA. However, there were significant inter-racial differences in serum IL-16 levels.

Newly Diagnosed Breast Cancer: Comparison of Contrast-enhanced Spectral Mammography and Breast MR Imaging in the Evaluation of Extent of Disease.

Purpose To compare the diagnostic performances of contrast material-enhanced spectral mammography and breast magnetic resonance (MR) imaging in the detection of index and secondary cancers in women with newly diagnosed breast cancer by using histologic or imaging follow-up as the standard of reference. Materials and Methods This institutional review board-approved, HIPAA-compliant, retrospective study included 52 women who underwent breast MR imaging and contrast-enhanced spectral mammography for newly diagnosed unilateral breast cancer between March 2014 and October 2015. Of those 52 patients, 46 were referred for contrast-enhanced spectral mammography and targeted ultrasonography because they had additional suspicious lesions at MR imaging. In six of the 52 patients, breast cancer had been diagnosed at an outside institution. These patients were referred for contrast-enhanced spectral mammography and targeted US as part of diagnostic imaging. Images from contrast-enhanced spectral mammography were analyzed by two fellowship-trained breast imagers with 2.5 years of experience with contrast-enhanced spectral mammography. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value were calculated for both imaging modalities and compared by using the Bennett statistic. Results Fifty-two women with 120 breast lesions were included for analysis (mean age, 50 years; range, 29-73 years). Contrast-enhanced spectral mammography had similar sensitivity to MR imaging (94% [66 of 70 lesions] vs 99% [69 of 70 lesions]), a significantly higher PPV than MR imaging (93% [66 of 71 lesions] vs 60% [69 of 115 lesions]), and fewer false-positive findings than MR imaging (five vs 45) (P < .001 for all results). In addition, contrast-enhanced spectral mammography depicted 11 of the 11 secondary cancers (100%) and MR imaging depicted 10 (91%). Conclusion Contrast-enhanced spectral mammography is potentially as sensitive as MR imaging in the evaluation of extent of disease in newly diagnosed breast cancer, with a higher PPV. © RSNA, 2017.

Low Compliance in a Health-Conscience Spending Era Likely Helps Obviates the Need for 6 month BI-RADS 3 Breast MRI Follow-up After 1 year.

The goal of our IRB-approved study was to assess if a follow-up MRI every 6 months for 2 years is the most appropriate short-interval follow-up schedule. 203 breast MRI exams were performed from October 2009 to January 2014 as part of a BI-RADS 3 follow-up representing 2.6% of all breast MRIs (7,822) performed. We performed a retrospective longitudinal medical records review of compliance; malignancy rate of BI-RADS 3 exams; and average time and number of breast MRIs necessary prior to definitive disposition. While 77.8% eventually returned, only 45.5% of patients were compliant with follow-up at or near 6 months (4.5-7.5 months). Of those who eventually returned, it took an average of 1.31 follow-up MRIs (95% CI: 1.20-1.43 exams) and 10.3 months (95% CI: 9.0-11.7 months) before definitive disposition. 93.5% of initial findings were dispositioned as benign after two follow-up MRI exams (malignancy rate: 0.98%). Our results lend support to the possibility that the follow-up interval for BI-RADS 3 breast MRIs could be lengthened to 12 months if additional follow-up MRIs are necessary after the first year of 6-month follow-up breast MRIs. Foremost, this appears to be a safe follow-up alternative since benign definitive disposition can usually be made in less than 1 year. Supplemental reasons include persistent low-patient compliance (as redemonstrated in our study) and the higher cost of breast MRI compared to mammogram/ultrasound follow-up. Finally, this paper's findings further support the suggested MRI follow-up interval in the newest BI-RADS atlas.

Concordance in the Assessment of Effectiveness of Palliative Care between Patients and Palliative Care Nurses in Malaysia: A Study with the Palliative Care Outcome Scale.

CONTEXT: The Palliative Care Outcome Scale (POS) is an easy-to-use assessment tool to evaluate the effectiveness of palliative care. There is no published literature on the use of POS as an assessment tool in Malaysia. AIM: To define the concordance in the assessment of quality of life between patients with advanced cancers and their palliative care nurses using a Malay version of the POS. SETTINGS AND DESIGN: This study was conducted in the palliative care unit of the Hospital Tuanku Ja'afar Seremban, Malaysia, from February 2014 to June 2014. SUBJECTS AND METHODS: We adapted and validated the English version of the 3-day recall POS into Malay and used it to define the concordance in the assessment of quality of life between patients and palliative care nurses. Forty patients with advanced stage cancers and forty palliative care nurses completed the Malay POS questionnaire. STATISTICAL ANALYSIS USED: The kappa statistical test was used to assess the agreement between patients and their palliative care nurses. RESULTS: Slight to fair concordance was found in all items, except for one item (family anxiety) where there was no agreement. CONCLUSIONS: The Malay version of the POS was well accepted and reliable as an assessment tool for evaluation of the effectiveness of palliative care in Malaysia. Slight to fair concordance was shown between the patients and their palliative care nurses, suggesting the needs for more training of the nurses.

Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: epidemiology, metabolism and the associated diseases.

The Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is associated with various diseases (vascular, cancers, neurology, diabetes, psoriasis, etc) with the epidemiology of the polymorphism of the C677T that varies dependent on the geography and ethnicity. The 5,10-Methylenetetrahydrofolate reductase (MTHFR) locus is mapped on chromosome 1 at the end of the short arm (1p36.6). This enzyme is important for the folate metabolism which is an integral process for cell metabolism in the DNA, RNA and protein methylation. The mutation of the MTHFR gene which causes the C677T polymorphism is located at exon 4 which results in the conversion of valine to alanine at codon 222, a common polymorphism that reduces the activity of this enzyme. The homozygous mutated subjects have higher homocysteine levels while the heterozygous mutated subjects have mildly raised homocysteine levels compared with the normal, non-mutated controls. Hyperhomocysteinemia is an emerging risk factor for various cardiovascular diseases and with the increasing significance of this polymorphism in view of the morbidity and mortality impact on the patients, further prevention strategies and nutritional recommendations with the supplementation of vitamin B12 and folic acid which reduces plasma homocysteine level would be necessary as part of future health education. This literature review therefore focuses on the recent evidence-based reports on the associations of the MTHFR C677T polymorphism and the various diseases globally.

Predictors of frequent oral analgesic use in rheumatoid arthritis.

OBJECTIVE: The main objective of this study was to determine the predictors of frequent oral analgesic use among Rheumatoid Arthritis (RA) patients who were prescribed with the above medication on an 'as-needed' basis. METHODS: Patients with RA were recruited consecutively from the Rheumatology outpatient clinics in this cross-sectional study. The sociodemographic data, frequency of oral analgesic intake, Patient Global Assessment (PGA) scores and HAQ (Health Assessment Questionnaire) scores were determined by interviewing the subjects. Subjects were divided into 2 groups; frequent users (3 days and above in a week) and less frequent users (less than 3 days in a week). RESULTS: In a total of 112 subjects, 39 (34.8%) were frequent analgesic users. Both the HAQ and PGA scores were significantly higher among the frequent users (p<0.05). Using multivariate analysis, the HAQ scores (p=0.015, odds ratio 3.161 [95% confidence interval of 1.246-8.015]) and PGA scores (p=0.039 odds ratio 1.291 [95% confidence interval of 1.012-1.646]) were found to be independent predictors of frequent analgesic use. CONCLUSIONS: Our study confirms that the frequency of analgesic intake in Rheumatoid Arthritis has a significant relationship with patient-reported functional capacity and well being.

Myocardial infarction false alarm: initial electrocardiogram and cardiac enzymes.

OBJECTIVE: The objectives of this study were to determine the incidence of a myocardial infarction "false alarm" and evaluate the efficacy of the initial electrocardiogram and cardiac enzymes in diagnosing myocardial infarction in Malaysia. METHODS: We recruited patients who were admitted with suspected myocardial infarction from June to August 2008. The medical records of these patients were reviewed for the initial electrocardiogram, initial cardiac enzyme levels (creatinine kinase-MB and troponin T), and the final diagnosis upon discharge. The subjects were stratified into 2 groups: true myocardial infarction, and false alarm. RESULTS: 125 patients were enrolled in this study. Following admission and further evaluation, the diagnosis was revised from myocardial infarction to other medical conditions in 48 (38.4%) patients. The sensitivity and specificity of the initial ischemic electrocardiographic changes were 54.5% and 70.8%, respectively. Raised cardiac enzymes had a sensitivity of 44.3% and specificity of 95.8%. CONCLUSION: A significant proportion of patients in Malaysia are admitted with a false-alarm myocardial infarction. The efficacy of the electrocardiogram in diagnosing myocardial infarction in Malaysia was comparable to the findings of Western studies, but the cardiac enzymes had a much lower sensitivity.