Urine Albumin-Creatinine Ratio Variability in People With Type 2 Diabetes: Clinical and Research Implications.

RATIONALE & OBJECTIVE: Evidence has demonstrated that albuminuria is a key diagnostic and prognostic marker of diabetic chronic kidney disease, but the impact of its day-to-day variability has not been adequately considered. This study quantified within-individual variability of albuminuria in people with type 2 diabetes to inform clinical albuminuria monitoring. STUDY DESIGN: Descriptive cross-sectional analysis. SETTING & PARTICIPANTS: People with type 2 diabetes (n=826, 67.1 [IQR, 60.3-72.4] years, 64.9% male) participating in the Progression of Diabetic Complications (PREDICT) cohort study. EXPOSURE: Four spot urine collections for measurement of urinary albumin-creatinine ratio (UACR) within 4 weeks. OUTCOME: Variability of UACR. ANALYTICAL APPROACH: We characterized within-individual variability (coefficient of variation [CV], 95% limits of random variation, intraclass correlation coefficient), developed a calculator displaying probabilities that any observed difference between a pair of UACR values truly exceeded a 30% difference, and estimated the ranges of diagnostic uncertainty to inform a need for additional UACR collections to exclude or confirm albuminuria. Multiple linear regression examined factors influencing UACR variability. RESULTS: We observed high within-individual variability (CV 48.8%; 95% limits of random variation showed a repeated UACR to be as high/low as 3.78/0.26 times the first). If a single-collection UACR increased from 2 to 5mg/mmol, the probability that UACR actually increased by at least 30% was only 50%, rising to 97% when 2 collections were obtained at each time point. The ranges of diagnostic uncertainty were 2.0-4.0mg/mmol after an initial UACR test, narrowing to 2.4-3.2 and 2.7-2.9mg/mmol for the mean of 2 and 3 collections, respectively. Some factors correlated with higher (female sex; moderately increased albuminuria) or lower (reduced estimated glomerular filtration rate and sodium-glucose cotransporter 2 inhibitor/angiotensin-converting enzyme inhibitor/angiotensin receptor blocker treatment) within-individual UACR variability. LIMITATIONS: Reliance on the mean of 4 UACR collections as the reference standard for albuminuria. CONCLUSIONS: UACR demonstrates a high degree of within-individual variability among individuals with type 2 diabetes. Multiple urine collections for UACR may improve capacity to monitor changes over time in clinical and research settings but may not be necessary for the diagnosis of albuminuria. PLAIN-LANGUAGE SUMMARY: Albuminuria (albumin in urine) is a diagnostic and prognostic marker of diabetic chronic kidney disease. However, albuminuria can vary within an individual from day to day. We compared 4 random spot urinary albumin-creatinine ratio (UACR) samples from 826 participants. We found that a second UACR collection may be as small as a fourth or as large as almost 4 times the first sample's UACR level. This high degree of variability presents a challenge to our ability to interpret changes in albuminuria. Multiple collections have been suggested as a solution. We have constructed tools that may aid clinicians in deciding how many urine collections are required to monitor and diagnose albuminuria. Multiple urine collections may be required for individual monitoring but not necessarily for diagnosis.

Glycaemic outcomes in hospital with IDegAsp versus BIAsp30 premixed insulins.

BACKGROUND AND AIMS: IDegAsp (Ryzodeg 70/30), a unique premixed formulation of long-acting insulin degludec and rapid-acting insulin aspart, is increasing in use. Management of IDegAsp during hospitalisation is challenging because of degludec's ultra-long duration of action. We investigated inpatient glycaemia in patients treated with IDegAsp compared to biphasic insulin aspart (BIAsp30; Novomix30). METHODS: We performed a retrospective observational study at two hospitals assessing inpatients with type 2 diabetes treated with IDegAsp or BIAsp30 prior to and during hospital admission. Standard inpatient glycaemic outcomes were analysed based on capillary blood glucose (BG) measurements. RESULTS: We assessed 88 individuals treated with IDegAsp and 88 HbA1c-matched individuals treated with BIAsp30. Patient characteristics, including insulin dose at admission, were well matched, but the IDegAsp group had less frequent twice-daily insulin dosing than the BIAsp30 group (49% vs 87%, P < 0.001). Patient-days with BG <4 mmol/L were not different (10.6% vs 9.9%, P = 0.7); however, the IDegAsp group had a higher patient-day mean BG (10.4 (SD 3.4) vs 10.0 (3.4) mmol/L, P < 0.001), and more patient-days with mean BG >10 mmol/L (48% vs 38%, P < 0.001) compared to the BIAsp30 group. Glucose was higher in the IDegAsp group in the evening (4 PM to midnight) (11.6 (SD 4.0) vs 10.9 (4.6) mmol/L, P = 0.004), but not different at other times during the day. CONCLUSIONS: Inpatients treated with IDegAsp compared to BIAsp30 had similar hypoglycaemia incidence, but higher hyperglycaemia incidence, potentially related to less frequent twice-daily dosing. With the increasing use of IDegAsp in the community, development of hospital management guidelines for this insulin formulation is needed.

Subclinical hypothyroidism during pregnancy: the Melbourne public hospitals consensus.

BACKGROUND: Interest in potential adverse outcomes associated with maternal subclinical hypothyroidism (normal free T4, elevated thyroid-stimulating hormone (TSH)) has increased significantly over recent years. In turn, the frequency of maternal thyroid function testing has risen, despite universal thyroid function screening not being recommended, leading to a marked increase in referrals to obstetric endocrinology clinics. In 2017 the American Thyroid Association revised their diagnostic and management guidelines. Although welcome, these new guidelines contain recommendations that may cause confusion in clinical practice. AIM: To ensure uniform practice in the diagnosis and management of subclinical hypothyroidism in pregnancy across all Melbourne public hospitals. METHODS: Endocrinology and obstetric representatives from all Melbourne public hospital networks reviewed the 2017 American Thyroid Association guidelines and other relevant literature to develop a consensus for diagnosing and treating subclinical hypothyroidism during pregnancy in Melbourne. The consensus guidelines were then referred to the Endocrine Society of Australia for comment and endorsement. RESULTS: Consensus was achieved and the guidelines were endorsed by the Council of the Endocrine Society of Australia. Trimester and assay-specific TSH reference intervals derived from healthy local populations should be used, where available. When unavailable, a TSH cut-off of 4 mU/L (replacing the previously recommended 2.5 mU/L) should be used to initiate treatment, irrespective of thyroid auto-antibody status. The recommended starting dose of levothyroxine is 50 µg daily, with a therapeutic TSH target of 0.1-2.5 mU/L. Levothyroxine should generally be ceased after delivery, with some exceptions. Hospitals will ensure smooth transfer of care back to the woman's general practitioner with clear documentation of pregnancy thyroid management and a recommended plan for follow-up. CONCLUSION: Fewer women will be classified as having subclinical hypothyroidism during pregnancy, which is likely to lead to reductions in emotional stress, hospital visits, repeated blood tests and financial costs. Uniform clinical practice will occur across Melbourne.

Retinal small vessel narrowing in women with gestational diabetes, pregnancy-associated hypertension, or small-for-gestational age babies.

Background: Gestational diabetes, pregnancy-associated hypertension and small-for-gestational age babies are all associated with impaired placental vascularisation. This study compared the effects of these conditions the systemic small vessel calibre that was examined in the retina. Methods: This was a cross-sectional observational study of consecutive pregnant women recruited from an antenatal clinic. Participants underwent a Glucose Tolerance Test, BP measurements, and were examined for small-for-gestational age babies as per national guidelines. They also underwent retinal photography with a non-mydriatic camera, and vessel calibres were measured with a validated semi-quantitative system at a retinal grading centre. Some participants also underwent testing of retinal vascular responsiveness to a flickering light. Results: Women with gestational diabetes (n = 68) had a higher mean arterial pressure (85 ± 9 mm Hg) than normal pregnant women (n = 27, 80 ± 8 mmHg, p = 0.01). They also had smaller mean retinal arteriole (147.5 ± 13.6 µm and 159.7 ± 6.7 µm respectively, p < 0.01) and venular calibre (221.0 ± 13.4 µm and 232.8 ± 20.1 µm respectively, p < 0.01) than normal. However their babies' mean birth weights were not different from normal (3,311 ± 558 g and 3,401 ± 600 g respectively, p = 0.48). They also demonstrated a trend to reduced retinal arteriolar dilatation (3.5 ± 1.3%, n = 23) in response to vasodilatory stimuli (4.4 ± 1.8%) (n = 11) (p = 0.08) consistent with endothelial dysfunction. Women with pregnancy-associated hypertension (n = 35) had a higher mean arterial pressure (101 ± 12 mm Hg, p < 0.01), a smaller mean retinal arteriolar calibre (139.9 ± 10.6 µm, p < 0.0001), and a lower baby mean birth weight than for normal pregnancies (3,095 ± 443 g, p = 0.02). Likewise, women with small-for-gestational age babies (n = 31) had a higher mean arterial pressure (89 ± 19 mm Hg, p = 0.03), a smaller mean retinal arteriolar calibre (141.6 ± 12.8 µm, p < 0.01) and a lower baby mean birth weight than for normal pregnancies (2,468 ± 324 g, p < 0.0001). Conclusion: Mean retinal arterial calibre was reduced in women with gestational diabetes, pregnancy-associated hypertension or small-for-gestational age babies. The reduction in calibre was greatest in pregnancy-associated hypertension and small-for-gestational age babies. Systemic arteriole narrowing may contribute to the pathogenesis of placental vascular dysfunction in these conditions.

Diabetic peripheral neuropathy in diabetic patients attending an urban health and training centre.

Introduction: Diabetic neuropathy is a complication affecting almost 50% of the diabetic patients. Diabetic Peripheral Neuropathy (DPN) predominantly affects the hands and lower limbs. It leads to loss of protective sensation resulting in continuous injury to insensitive feet. The early detection of DPN using an objective screening test followed by its appropriate management is important as up to 50% of the patients may be asymptomatic. Objectives: To screen Diabetic patients attending an Urban Health and Training Centre of a medical college in Tamilnadu for Diabetic Peripheral Neuropathy. To assess the association between DPN and selected variables such as socio-demographic factors, glycaemic control, duration of diabetes, physical activity, body mass index, smoking and consumption of alcohol. Methods: The study was conducted among 204 diabetic patients attending an Urban Health and Training Centre. Participants were assessed using Michigan Neuropathy Screening Instrument (MNSI), which involves using a questionnaire followed by a physical examination. Results: Of the 204 patients, 58.8% were male. The mean age was 54.8 years (SD = 8.8 years). About 79.9% were employed of which 29.4% were skilled labourers. Mean duration of diabetes was 6.2 years (SD = 5.3 years). The proportion of diabetics who screened positive for Peripheral Neuropathy was 23% and 45.6% using MNSI questionnaire and examination, respectively. An age of 60 years and above was significantly associated with DPN (OR = 2.505, P value = 0.003). A duration of more than 4 years of diabetes was also significantly associated with DPN (OR = 1.872, P value = 0.02820). Conclusion: A high proportion of diabetics with peripheral neuropathy did not express symptoms specific for diabetics. Thus, a simple tool like MNSI would be useful in primary care settings to screen for peripheral neuropathy, and hence prevent disability".

Imaging and pathological discordance amongst the plethora of breast lesions in breast biopsies.

INTRODUCTION: Imaging-guided breast tissue biopsy has become an acceptable alternative to open surgical biopsy for nonpalpable breast lesions. Discussion of abnormal results of the correlation between imaging and pathological findings can be very challenging as it can assist in decision-making with regard to the further treatment options by arriving at a comprehensive diagnosis. MATERIALS AND METHODS: This was a retrospective study. Radiological data from imaging-guided breast biopsies of 500 patients during a 6-year period was collected and classified by a specialist radiologist as per the BI-RADS format. Histopathology reports were studied and discordance analyzed. RESULTS: A total of 500 cases were reviewed. Approximately 33% (168) cases fell into the BI-RADS 3 category, 24.4% (122) into the BI-RADS 4, and 37% (187) into BI-RADS 5 categories. Approximately 50% (n = 250) cases were benign, 2.6% (13) belonged to the high-risk category, and 47.4% (237) were malignant. The number of discordant cases was 12 (2.4%), mostly due to technical factors. Sensitivity of biopsies to detect malignancy was 85%, specificity was 96%, and accuracy of biopsy in diagnosing cancer was 90%. DISCUSSION: The "triple assessment" is the most sensitive method for detecting early breast cancer. An effective communication pathway must be established between a clinician, radiologist, and pathologist for surgical excision in discordance as it carries a high prevalence of carcinoma in these lesions. CONCLUSION: In discordant cases, either due to abnormal results of imaging or of abnormal pathological findings, the final decision is based on two concordant findings, out of the three parameters. This involves a multidisciplinary breast conference and an active participation by the pathologist.

Global coagulation assays in patients with diabetes mellitus.

BACKGROUND: There is significant heterogeneity in the incidence and severity of diabetes-associated vascular complications and there is no routine biomarker that accurately predicts these outcomes. This pilot study investigates the role of global coagulation assays in patients with diabetes mellitus. METHODS: In this cross-sectional study, patients with diabetes not on anticoagulation or dialysis and without active malignancy were recruited from endocrinology clinics. Blood samples were collected for global coagulation assays including thromboelastography (TEG), thrombin generation using calibrated automated thrombogram (CAT), and fibrin generation and fibrinolysis using the overall hemostatic potential (OHP) assay. The results were compared with healthy controls. RESULTS: A total of 147 adult patients including 19 with type 1 diabetes (T1DM), 120 with type 2 diabetes (T2DM), and eight with latent autoimmune diabetes were recruited. Compared with 153 healthy controls, patients with diabetes demonstrated higher maximum amplitude (68.6 vs 60.2 mm, p < 0.001) on TEG, and higher OHP (9.3 vs 6.4, p < 0.001) with comparable CAT parameters. Patients with T2DM were more hypercoagulable than those with T1DM on most biomarkers. Higher maximum amplitude, velocity index, and OHP were associated with increased risk of complications (C-stat 0.82). Patients with history of microvascular complications appear to have more hypercoagulable thrombin and fibrin generation than those without. CONCLUSION: Patients with diabetes have more hypercoagulable profiles on global coagulation assays, particularly patients with T2DM and those with microvascular complications. Further studies with longitudinal follow-up are ongoing to evaluate the utility of global coagulation assays in predicting long-term patient outcomes.

Beware Ketoacidosis with SGLT2 Inhibitors in Latent Autoimmune Diabetes of the Adult.

BACKGROUND: Sodium-glucose co-transporter-2 (SGLT2) inhibitors are increasingly used for the treatment of type 2 diabetes, but have been associated with ketoacidosis. METHODS/RESULTS: We report a case series of three patients with latent autoimmune diabetes of the adult who presented with ketoacidosis, including one case with normal blood glucose levels, in the context of SGLT2 inhibitor use. CONCLUSIONS: Sodium-glucose co-transporter-2 inhibitors should be used with caution and close clinical monitoring in patients with latent autoimmune diabetes of the adult. A clinical risk score permits targeted autoantibody testing and should be undertaken prior to commencement of SGLT2 inhibitors or cessation of insulin.

MR-guided focused ultrasound surgery: A novel non-invasive technique in the treatment of adenomyosis -18 month's follow-up of 12 cases.

BACKGROUND: Adenomyosis is a gynecological condition of the uterus, characterized by the presence of ectopic endometrial tissue in the myometrium. Hysterectomy, uterine artery embolization, and endometrial ablation therapy are the various surgical treatment options available for adenomyosis. A novel and globally upcoming technique is MR-guided focused ultrasound surgery "MRgFUS," which is a promising non-invasive surgical treatment option. This study was carried out to determine the effectiveness of MRgFUS in the symptomatic management of adenomyosis. SUBJECTS AND METHODS: This study was carried out as a long-term follow-up study among 12 cases of adenomyosis, which were treated by MR-guided focused ultrasound. In all these participant's, three parameters - symptom severity score (SSS), menstrual pain score accessed using visual analogue score (VAS), and number of approximate pads used during menstruation were recorded prior to the treatment and on follow-up at 3, 9, and 18 months, respectively. The Friedman's test was used to test the difference in the values of scores before and after treatment. RESULTS: There was a significant improvement in the SSS, VAS, and the numbers of sanitary napkins used after surgery and sustained during the long-term follow-up. These values were statistically significant (P < 0.05). CONCLUSION: MRgFUS can be used in successful treatment of adenomyosis/focal adenomyoma by careful selection of the participant, good planning, and proper monitoring of the technique during ablation.

SGLT2 Inhibitors Increase the Risk of Diabetic Ketoacidosis Developing in the Community and During Hospital Admission.

CONTEXT: Diabetic ketoacidosis (DKA) has been associated with the use of sodium glucose cotransporter 2 inhibitors (SGLT2is). OBJECTIVE: To determine the incidence, characteristics, and outcomes of DKA in SGLT2i users vs nonusers with type 2 diabetes. DESIGN: Retrospective, multicenter, controlled cohort study. SETTING: All public hospitals in Melbourne and Geelong (combined population of 5 million), Australia, from 1 September 2015 to 31 October 2017. PATIENTS: Consecutive cases of DKA that developed in the community, or during the course of hospital admission, in patients with type 2 diabetes. MAIN OUTCOME MEASURES: In SGLT2i users vs nonusers: (i) OR of DKA developing during hospital admission, and (ii) incidence of DKA. RESULTS: There were 162 cases of DKA (37 SGLT2i users and 125 non-SGLT2i users) with a physician-adjudicated diagnosis of type 2 diabetes. Of these, DKA developed during the course of inpatient admission in 14 (38%) SGLT2i users vs 2 (2%) non-SGLT2i users (OR, 37.4; 95% CI, 8.0 to 175.9; P < 0.0001). The incidence of DKA was 1.02 per 1000 (95% CI, 0.74 to 1.41 per 1000) in SGLT2i users vs 0.69 per 1000 (95% CI, 0.58 to 0.82 per 1000) in non-SGLT2i users (OR, 1.48; 95% CI, 1.02 to 2.15; P = 0.037). Fifteen SGLT2i users (41%) had peak blood glucose <250 mg/dL (14 mmol/L) compared with one (0.8%) non-SGLT2i user (P < 0.001). CONCLUSIONS: SGLT2i users were more likely to develop DKA as an inpatient compared with non-SGLT2i users. SGLT2i use was associated with a small but significant increased risk of DKA.

An Endocrine Cause of Acute Post-partum Hypertension.

This is a case of acute peri-partum hypertension secondary to Conn's syndrome. The timing of presentation offers a rare insight into the hormonal physiology of pregnancy and its impact on blood pressure regulation. This case highlights the challenges of diagnosing primary hyperaldosteronism in the peripartum period and the high index of suspicion required by the obstetric physician.

The role of immunohistochemistry in the analysis of the spectrum of small round cell tumours at a tertiary care centre.

CONTEXT: The term, "Small Round - Cell Tumours" (SRCT) describes a group of highly aggressive malignant neoplasms which are composed predominantly of small and monotonous undifferentiated cells with high nucleocytoplasmic ratios. Immunohistochemistry (IHC) plays a crucial role in catagorizing the small round - cell tumours. AIMS: This study was done to analyse the spectrum of small round cell tumours over a period of five years at a tertiary care centre and to study the relevance of immunohistochemistry in making precise diagnoses of the small round cell tumours. MATERIAL AND METHODS: Formalin - fixed, paraffin - embedded sections of tumours which were diagnosed as small round cell tumours on small biopsies and resected specimens were retrieved from the files of the Department of Pathology of Sri Ramachandra Medical College and Research institute, in the period from January 2005 to December 2009. This study was confined to the bone and the soft tissues. Decalcification was performed on the bony tissues before the routine processing was done. The patients belonging to all age groups were included in this study. The small round cell tumours of the bone marrow, the spleen and the lymph node was excluded from our study. Immunohistochemical stains were performed to differentiate and categorise the small round blue cell tumours. The immunomarkers which were utilised in this study included CD45/LCA (the lymphocyte common antigen), CD20, CD3, CD99 (cluster of differentiation 99 also known as MIC2), desmin, EMA (epithelial membrane antigen), CK(cytokeratin), synaptophysin, chromogranin and GFAP (Glial fibrillary acidic protein). RESULTS: Forty three cases of small round cell tumours were analysed, which included 19 cases of NHL (non Hodgkin's lymphoma), 6 cases of Ewing/PNETs (primitive neuroectodermal tumours), 3 cases of atypical carcinoid, 3 cases of olfactory neuroblastoma, 2 cases each of rhabdomyosarcoma, Wilms tumour, neuroblastoma and synovial sarcoma and 1 case each of small cell osteosarcoma, small (oat) cell carcinoma, medulloblastoma and hepatoblastoma. By using a panel of monoclonal antibodies, we could arrive at a final diagnosis for all the 40 cases in which immunohistochemistry was performed. CONCLUSION: Our study showed that the use of immunohistochemistry was extremely beneficial. A majority of the small round cell tumours occurred between the ages of 15-45 years and the most common small round cell tumour was Non-Hodgkins lymphoma (extra lymphoreticular).

Hypocalcemia induced by raloxifene.

Raloxifene is an anti-resorptive agent used in postmenopausal osteoporosis. This is the first report of the occurrence of clinically significant hypocalcemia following raloxifene treatment in a patient with occult vitamin D deficiency. Since vitamin D deficiency is widely prevalent in the community, screening for vitamin D deficiency and its correction is advisable before the initiation of anti-resorptive therapy.