Open randomised controlled interventional prospective study to evaluate the role of prophylactic calcium and vitamin D in preventing short term steroid induced bone loss in new onset nephrotic syndrome

INTRODUCTION: Nephrotic Syndrome is a common glomerular disorder affecting children. It is characterized by heavy proteinuria, hypoalbuminemia, edema and hypercholesterolemia. The incidence is 2-3 per 1, 00,000 children per year. Approximately 90% of children with Nephrotic Syndrome have some form Idiopathic Nephrotic Syndrome. This includes 3 histological types: 1. Minimal Change Disease. 2. Mesangial Proliferative Glomerulonephritis (MesPGN). 3. Focal Segmental Glomerulosclerosis. Corticosteroids like Prednisolone are the recommended first line treatment for nephrotic syndrome. Majority of children have Steroid Sensitive Minimal Change Disease. Most children with Steroid Sensitive Nephrotic Syndrome (SSNS) have repeated relapses, which generally decrease in frequency as the child grows older. Glucocorticoids are used in myriad other pediatric diseases. It is estimated that 10% of children may require some form of glucocorticoids at some point in their childhood. Prolonged steroid use is known to cause osteoporosis. Decreased bone mineral density (BMD) has been described in various pediatric disorders that require glucocorticoids, including asthma, juvenile rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, and organ transplantation . Impairment of childhood growth with an approximate cortisone dose of 1.5 mg/kg/day was first described over 40 years ago; osteopenia in children receiving a Prednisolone dose of less than 0.16 mg/kg/day has also been reported. 37,000 children were studied in UK by Van Staa et al, to evaluate the incidence of fractures among pediatric glucocorticoid users .Results showed that the risk of fracture was increased in children who received four or more courses of oral corticosteroids for a mean duration of 6.4 days. Fracture risk was also increased among children using 30 mg Prednisolone or more each day. Childhood Steroid sensitive nephrotic syndrome provides a clinical model of chronic glucocorticoid therapy in the absence of significant underlying disease activity. The course of SSNS is characterized by relapses which result in protracted, repeated courses of glucocorticoids. The standard Prednisolone dose for new onset disease and relapses is 2 mg/kg per day which far exceeds the 5 mg/day that is considered a risk factor for Glucocorticoid induced osteoporosis in adults. While osteoporosis has long been considered a disease of the aging, there is increasing awareness that children are not exempt from developing the disease. Threats to bone health that are operative during the pediatric years may be particularly costly long-term, since growth and development of the skeletal system play a critical role in determining bone strength and stability in later years. Although the deteriorative effect of steroid treatment on children’s bones has been well known for years, no recommendations have been suggested for the prevention of diminished BMD and BMC in children with nephrotic syndrome. There are no clear cut guidelines as to when bone protective strategies must be instituted. This study was thus undertaken to determine the protective efficacy of Calcium and Vitamin D supplementation in children with Nephrotic Syndrome on short term steroids. Using Bone Mineral Density (BMD) and Bone Mineral Content (BMC) as tools, those receiving supplementation were compared with those not receiving it. The results will enable us to draw protocols / guidelines for institution of bone protective therapy for children on short term steroids. AIM OF THE STUDY: To study the effect of short term corticosteroid therapy and the prophylactic role of Calcium and Vitamin D on bone health in children with nephrotic syndrome. OBJECTIVES: PRIMARY OBJECTIVES: 1. To study the effect of short term steroids on bone in children with nephrotic syndrome using serial measurements of Bone Mineral Density (BMD) & Bone Mineral Content (BMC)at the Lumbar spine. 2. To evaluate the role of prophylactic Calcium and Vitamin D in preventing short term steroid induced bone loss in children with new onset Nephrotic Syndrome. SECONDARY OBJECTIVE: 1. To study the adverse effects of steroid therapy. METHODOLOGY: Study Design and Duration: This open randomised controlled interventional prospective study was conducted in the Paediatric Nephrology and Endocrine Departments of Christian Medical College Hospital, Vellore. The study was conducted for a duration of 3 months from May 2007 to July 2008. Selection of Subjects: Children with new onset nephrotic syndrome were recruited into the study. Inclusion Criteria: 1. Patients in the age group of 1 to 13 years. 2. Children with first presentation of Nephrotic syndrome. 3.(Proteinuria more than 40 mg / m2 /hr or Urine spot protein/creatinine ratio of >2). 4.No history of prior steroid use. 5. No clinical or biochemical evidence of metabolic bone disease. Exclusion Criteria: 1. Patients with a history of previously known kidney or bone disease. 2. Patients with a history, clinical or biochemical evidence of metabolic bone disease (e.g. chronic renal failure, liver disease). 3. Children not fulfilling the criteria for Nephrotic syndrome (with gross hematuria, persistent hypertension or evidence of renal disease other than nephrotic syndrome). 4. Patients with a serum creatinine > 1.5 mg/dl. 5. Patients who were on or had received glucocorticoid therapy. 6. Children with onset of puberty - Tanner stage >1. 7. Patients on steroid sparing immunosuppression (Azathioprine, Mycophenolate. Mofetil, Cyclophosphamide, Cyclosporine). 8. Patients with known or suspected history of hypersensitivity to Prednisolone. SUMMARY: 46 children were recruited into the study and followed up over 12 weeks. 34 children had completed the study at the time of analysis, 4 were dropouts and 8 are still undergoing treatment. The children were randomized into 2 groups: Group 1: 18 children received steroids and Calcium and Vitamin D, Group 2: 16 children received steroids only. • Children in the age group of 1 year to 12.42 years were recruited into the study over a period of 15 months. The mean age was 4.13 years. Group 1 and Group 2 had similar age distribution. • There were 24 boys and 10 girls. The male: female ratio was 2.4: 1. • Majority of the children belonged to Tamil Nadu (24), followed by West Bengal (5), Jharkhand (2) , Tripura (2) and Andhra Pradesh (1). • In 35% (12/34) children, infections triggered onset, majority being LRI (6/12), followed by URI (4/12). 1 each had Acute Gastroenteritis, Hepatitis A and Urinary Tract Infection. • 20.6% (7/34) children had hypertension at onset. • By 2 weeks, 82.4% (28/34) children were in remission, 88.2% (30/34) by 4 weeks and 97% (33/34) by 6 weeks. • By 12weeks, 91.2% (31/34) remained in remission. • 38.6% (13/34) patients relapsed, 85% after stopping steroids and 15% while tapering steroids. In 46% (6/13), relapse was triggered by an infection. Viral fever and URI were the most common infections precipitating relapse. • Cushingoid features (100%), gastritis (79.4%), hypertrichosis (67.8%) and infections (20.6%) were the most commonly observed side effects of steroids. 8.8% had behavior changes and 5.9% had striae. • Higher incidence of gastritis and infections at 6 weeks compared to 12 weeks may reflect dose dependent nature of these side effects. • 76.4% (26/34) received additional medications in the form of diuretics – spironolactone (64.7%) and frusemide (50%), antibiotics (41.2%), antihypertensives – nifedipine (14.7%), atenolol (2.9%) and ATT (2.9%). • Change in Weight, Height and BMI and Serum Calcium over 12 weeks calculated over baseline showed no statistically significant difference between the 2 groups. • A net weight gain of 1.24 % in Group I and 7.7% in Group II was observed. • Group I & II showed 1.88 % and 2.11 % increase in height respectively. • BMI decreased by 1.78 % in Group I; in Group II it increased by 3.826% • Serum Calcium (corrected for the corresponding Serum albumin) was maintained in the normal physiological range in all children. • Serum Calcium dropped by 1.16% in Group I and 0.69 % in Group II. Despite the drop, Serum calcium values remained within the normal range at 12 weeks. • There was a small gain in BMD in both groups 2.77% in Group I and 1.63% in Group II. The difference between the 2 Groups was not significant. • Children receiving Calcium and Vitamin D supplements showed a marked increase in BMC (11.3%) in contrast to controls who showed a 10.4 % fall in the same. The difference in the 2 groups was highly significant ( z = - 4.175 , p < 0.001). • The net intervention (Ca & Vitamin D administration) attributable difference in Bone. • Mineral Content in the 2 groups was 21.6%. CONCLUSIONS: 1. Bone Mineral Content of growing children decreased by 10% after 12 weeks of steroid therapy in the control group confirming the detrimental effects of high dose short term steroids on the bone. 2. BMD increased only marginally both in absolute value as well as a percentage change over baseline in both treatment and control groups. BMD measurements failed to detect steroid induced bone changes in our study. This confirms the superiority of BMC rather than BMD in determining changes in bone health in growing children. 3. Children receiving Calcium and Vitamin D supplements showed a significant improvement (11.3%) in the BMC in contrast to controls who showed a 10% decrease in the same. 4. Prophylactic Calcium and Vitamin D supplementation is useful in preventing steroid induced bone changes as demonstrated by a net treatment attributable change in BMC of 21.6%. 5. Short term steroid therapy had minor adverse effects - Cushingoid features, Gastritis and Hypertrichosis being the most common. Infections were the only serious adverse effect noted

Study of the clinical spectrum of AUB (FIGO AUB Systems) and women’s attitude towards its management at Anugrah Narayan Magadh Medical College and Hospital, Gaya, Bihar, India

Background: AUB has significant impact on quality of life of women related to health specially in developing countries including India. FIGO AUB systems are universally accepted. Aim was to study the clinical spectrum of AUB according to the FIGO AUB systems and women’s attitude towards its management.Methods: Cross sectional prospective study was carried out in the department of Obstetrics and Gynaecology, ANMMCH, Gaya, a tertiary care center, among women of 15-55 years age groups having complain related to abnormal uterine bleeding, for 1 year from 1st May 2019 to 30th April 2020 on 1000 patients. Data was collected and analyzed by percentage and proportions.Results: Prevalence of AUB was maximum among 15-30 years age group of patients (46.80%). Most of the patients belong to lower (62.5%) class, rural area (68%) and were anaemic (62.5%). Ovulatory dysfunction (55%) was most common cause for AUB, maximum patients choose surgical management (hysterectomy) but after counselling, most of them shifted to medical management.Conclusions: This study suggests more conservative approach for management of AUB and emphasizes the importance of awareness for clinical spectrum of AUB among women so that they can be self-motivated for early treatment and unnecessary hysterectomy can be avoided

A comparative study for efficacy and safety of low doses of clonidine for hemodynamic stability in patients undergoing laparoscopic cholecystectomy

Background: This randomized prospective double-blind study was designed to evaluate the efficacy and side effects of low doses clonidine for perioperative haemodynamic stability and postoperative recovery.Methods: Patient’s with ASA grade I–II undergoing laparoscopic cholecystectomy were randomized into three groups of 30 patients each. All patients received either normal saline 10 ml (Group I) or 0.8 µg/kg (Group II) or 1 µg/kg (Group III) over duration of 180 seconds, 10 min prior to laryngoscopy and intubation. Anaesthesia was induced with 1% propofol (2 mg/kg) and maintained with nitrous oxide 60% in oxygen and isoflurane. The parameters assessed at various time intervals were heart rate, systolic blood pressure, diastolic blood pressure, mean arterial pressure and sedation score.Results: Both doses of clonidine proved to be effective in perioperative haemodynamic stability. Clonidine 0.8 mcg/kg was as effectve and safer to Clonidine 1 mcg/kg for attenuatíon of the hemodynamíc responses to laparoscopy. There were no significant differences in the parameters of recovery between groups.Conclusions: Significant hemodynamic derangements can occur during laproscopic cholecystectomy at intubation, pneumoperitoneum and extubation. These were effectively attenuated by premedication with 0.8 mcg/kg and 1 mcg/kg of intravenous clonidine. Dose of 1 mcg/kg though found to be effective but produced adverse effects in form of hypotension and bradycardia

Stability of Unicortical versus Bicortical Metacarpal Fracture Internal Fixation Trial (SUBMIT): study protocol for a randomized controlled trial

BACKGROUND: Metacarpal fractures are common, accounting for 40 % of all hand injuries. The use of plates for the fixation of these fractures allows early aggressive hand therapy post-operatively, reducing post-operative stiffness. Traditionally, bicortical fixation is the standard practice, where both dorsal and palmar cortices of the metacarpal are drilled through, with screws engaging both cortices. Recent biomechanical studies have shown that unicortical fixation, where only the near cortex is drilled and engaged by the screw, results in no difference in stiffness, load to failure or failure mechanism, when compared with bicortical fixation. This trial aims to compare fracture union, complication rate and functional outcomes between unicortical and bicortical fixation for adults with displaced metacarpal fractures. METHODS/DESIGN: All adults with displaced diaphyseal metacarpal fracture requiring plate fixation are potentially eligible to take part in this study. A total of 315 consenting patients will be randomly allocated to either unicortical or bicortical plate and screw fixation. The surgery will be performed in specialist hand trauma units across the UK. Data regarding fracture healing, hand function, quality of life, and complications will be collected at 2 weeks, 6 weeks and 6 months following surgery. DISCUSSION: This pragmatic, prospective, multi-centre, randomized controlled trial is expected to deliver results in 2018. TRIAL REGISTRATION: ISRCTN 18006607. Registered on 19 Nov 2015

The Impact of Slice Interval and Equation on the Accuracy of Magnetic Resonance Image Estimation of Quadriceps Muscle Volume in End Stage Liver Disease

INTRODUCTION: End stage liver disease (ESLD) is associated with loss of muscle mass and function, known as sarcopenia, which can increase the risk of complications of ESLD, hospitalization and mortality. Therefore, the accurate assessment of muscle mass is essential to evaluate sarcopenia in ESLD. However, manual segmentation of muscle volume (MV) can be laborious on cross-sectional imaging, due to the number of slices that require analysis. This study aimed to investigate the impact of reducing the number of slices required for MV estimation. Further, we aimed to compare two equations utilized in estimating MV (cylindrical and truncated cone). METHODS: Thirty eight ESLD patients (23 males; 54.8 ± 10.7 years) were recruited from the Queen Elizabeth University Hospital Birmingham. A 3T MRI scan was completed of the lower limbs. Quadriceps MV was estimated utilizing 1-, 2-, 3-, and 4 cm slice intervals with both cylindrical and truncated cone equations. Absolute and relative error (compared to 1 cm slice interval) was generated for 2-, 3-, and 4 cm slice intervals. L3 skeletal muscle index (SMI) was also calculated in 30 patients. RESULTS: Relative error increased with slice interval using the cylindrical (0.45 vs. 1.06 vs. 1.72%) and truncated cone equation (0.27 vs. 0.58 vs. 0.74%) for 2, 3, and 4 cm, respectively. Significantly, the cylindrical equation produced approximately twice the error compared to truncated cone, with 3 cm (0.58 vs. 1.06%, P < 0.01) and 4 cm intervals (0.74 vs. 1.72%, P < 0.001). Finally, quadriceps MV was significantly correlated to L3 SMI (r(2) = 0.44, P < 0.0001). CONCLUSION: The use of the truncated equation with a 4 cm slice interval on MRI offers an efficient but accurate estimation of quadricep muscle volume in ESLD patients

Scaphoid Waist Internal Fixation for Fractures Trial (SWIFFT) protocol : a pragmatic multi-centre randomised controlled trial of cast treatment versus surgical fixation for the treatment of bi-cortical, minimally displaced fractures of the scaphoid waist in adults

BACKGROUND: A scaphoid fracture is the most common type of carpal fracture affecting young active people. The optimal management of this fracture is uncertain. When treated with a cast, 88 to 90 % of these fractures unite; however, for the remaining 10-12 % the non-union almost invariably leads to arthritis. The alternative is surgery to fix the scaphoid with a screw at the outset. METHODS/DESIGN: We will conduct a randomised controlled trial (RCT) of 438 adult patients with a "clear" and "bicortical" scaphoid waist fracture on plain radiographs to evaluate the clinical effectiveness and cost-effectiveness of plaster cast treatment (with fixation of those that fail to unite) versus early surgical fixation. The plaster cast treatment will be immobilisation in a below elbow cast for 6 to 10 weeks followed by mobilisation. If non-union is confirmed on plain radiographs and/or Computerised Tomogram at 6 to 12 weeks, then urgent surgical fixation will be performed. This is being compared with immediate surgical fixation with surgeons using their preferred technique and implant. These treatments will be undertaken in trauma units across the United Kingdom. The primary outcome and end-point will be the Patient Rated Wrist Evaluation (a patient self-reported assessment of wrist pain and function) at 52 weeks and also measured at 6, 12, 26 weeks and 5 years. Secondary outcomes include an assessment of radiological union of the fracture; quality of life; recovery of wrist range and strength; and complications. We will also qualitatively investigate patient experiences of their treatment. DISCUSSION: Scaphoid fractures are an important public health problem as they predominantly affect young active individuals in the more productive working years of their lives. Non-union, if untreated, can lead to arthritis which can disable patients at a very young age. There is a rapidly increasing trend for immediate surgical fixation of these fractures but there is insufficient evidence from existing RCTs to support this. The SWIFFT Trial is a rigorously designed and adequately powered study which aims to contribute to the evidence-base to inform clinical decisions for the treatment of this common fracture in adults. TRIAL REGISTRATION: The trial is registered with the International Standard Randomised Controlled Trial Register ( ISRCTN67901257 ). Date registration assigned was 13/02/2013

The Impact of Slice Interval and Equation on the Accuracy of Magnetic Resonance Image Estimation of Quadriceps Muscle Volume in End Stage Liver Disease

IntroductionEnd stage liver disease (ESLD) is associated with loss of muscle mass and function, known as sarcopenia, which can increase the risk of complications of ESLD, hospitalization and mortality. Therefore, the accurate assessment of muscle mass is essential to evaluate sarcopenia in ESLD. However, manual segmentation of muscle volume (MV) can be laborious on cross-sectional imaging, due to the number of slices that require analysis. This study aimed to investigate the impact of reducing the number of slices required for MV estimation. Further, we aimed to compare two equations utilized in estimating MV (cylindrical and truncated cone).MethodsThirty eight ESLD patients (23 males; 54.8 ± 10.7 years) were recruited from the Queen Elizabeth University Hospital Birmingham. A 3T MRI scan was completed of the lower limbs. Quadriceps MV was estimated utilizing 1-, 2-, 3-, and 4 cm slice intervals with both cylindrical and truncated cone equations. Absolute and relative error (compared to 1 cm slice interval) was generated for 2-, 3-, and 4 cm slice intervals. L3 skeletal muscle index (SMI) was also calculated in 30 patients.ResultsRelative error increased with slice interval using the cylindrical (0.45 vs. 1.06 vs. 1.72%) and truncated cone equation (0.27 vs. 0.58 vs. 0.74%) for 2, 3, and 4 cm, respectively. Significantly, the cylindrical equation produced approximately twice the error compared to truncated cone, with 3 cm (0.58 vs. 1.06%, P &lt; 0.01) and 4 cm intervals (0.74 vs. 1.72%, P &lt; 0.001). Finally, quadriceps MV was significantly correlated to L3 SMI (r2 = 0.44, P &lt; 0.0001).ConclusionThe use of the truncated equation with a 4 cm slice interval on MRI offers an efficient but accurate estimation of quadricep muscle volume in ESLD patients

A VALIDATED RP-UPLC METHOD DEVELOPMENT FOR SIMULTANEOUS ESTIMATION OF LANSOPRAZOLE AND NAPROXEN IN BULK AND TABLET DOSAGE FORM

Objective:  A simple and precise RP-UPLC method development and validation for simultaneous estimation of lansoprazole (LAN) and naproxen (NAP) in bulk and tablet Dosage Form.Method: Simple, accurate and cost efficient RP-UPLC method has been developed and validated for the simultaneous estimation of lansoprazole and naproxen in bulk and tablet dosage form.  The optimum conditions for the analysis of the drug were established.Results: The retention time (RT) was found to be 3.905 and 2.650 min for lansoprazole (LAN) and naproxen (NAP), for analysis the maximum wavelength (λmax) was found 284nm for simultaneous estimation of LAN and NAP. The method was linear and found to be range between 5-30 μg/ml (r2= 0.998) and 10-35 μg/ml (r2= 0.999) for LAN and NAP respectively. The value of limit of detection and limit of quantification was 0.8397 and 2.979 μg/ml for LAN and 0.4678 and 1.5593 μg/ml for NAP, the recovery was found between 80,100 and 120% and RSD less than 2 for LAN and NAP. The method was satisfactorily validated as per the ICH guideline.Conclusion: The proposed methods were simple, sensitive, precise, accurate, reproducible, quick and useful for routine quality control. This study shows that the proposed RP-UPLC method is useful for the routine determination of LAN and NAP in its bulk and tablet dosage form.Keywords: Lansoprazole, Naproxen, RP-UPLC, Method validation and TabletsÂ