Manit Arora

Clinical Pharmacokinetics of Metformin

Metformin is widely used for the treatment of type 2 diabetes mellitus. It is a biguanide developed from galegine, a guanidine derivative found in Galega officinalis (French lilac). Chemically, it is a hydrophilic base which exists at physiological pH as the cationic species (>99.9%). Consequently, its passive diffusion through cell membranes should be very limited. The mean ± SD fractional oral bioavailability (F) of metformin is 55 ± 16%. It is absorbed predominately from the small intestine.Metformin is excreted unchanged in urine. The elimination half-life (t1/2) of metformin during multiple dosages in patients with good renal function is approximately 5 hours. From published data on the pharmacokinetics of metformin, the population mean of its clearances were calculated. The population mean renal clearance (CLR) and apparent total clearance after oral administration (CL/F) of metformin were estimated to be 510 ± 130 mL/min and 1140 ± 330 mL/min, respectively, in healthy subjects and diabetic patients with good renal function. Over a range of renal function, the population mean values of CLR and CL/F of metformin are 4.3 ± 1.5 and 10.7 ± 3.5 times as great, respectively, as the clearance of creatinine (CLCR). AS the CLR and CL/F decrease approximately in proportion to CLCR, the dosage of metformin should be reduced in patients with renal impairment in proportion to the reduced CLCR.The oral absorption, hepatic uptake and renal excretion of metformin are mediated very largely by organic cation transporters (OCTs). An intron variant of OCT1 (single nucleotide polymorphism [SNP] rs622342) has been associated with a decreased effect on blood glucose in heterozygotes and a lack of effect of metformin on plasma glucose in homozygotes. An intron variant of multidrug and toxin extrusion transporter [MATE1] (G>A, SNP rs2289669) has also been associated with a small increase in antihyperglycaemic effect of metformin. Overall, the effect of structural variants of OCTs and other cation transporters on the pharmacokinetics of metformin appears small and the subsequent effects on clinical response are also limited. However, intersubject differences in the levels of expression of OCT1 and OCT3 in the liver are very large and may contribute more to the variations in the hepatic uptake and clinical effect of metformin.Lactic acidosis is the feared adverse effect of the biguanide drugs but its incidence is very low in patients treated with metformin. We suggest that the mean plasma concentrations of metformin over a dosage interval be maintained below 2.5 mg/L in order to minimize the development of this adverse effect.

Review article: Burnout in emergency medicine physicians

Training and the practice of emergency medicine are stressful endeavours, placing emergency medicine physicians at risk of burnout. Burnout syndrome is associated with negative outcomes for patients, institutions and the physician. The aim of this review is to summarise the available literature on burnout among emergency medicine physicians and provide recommendations for future work in this field. A search of MEDLINE (1946–present) (search terms: ‘Burnout, Professional’ AND ‘Emergency Medicine’ AND ‘Physicians’; ‘Stress, Psychological’ AND ‘Emergency Medicine’ AND ‘Physicians’) and EMBASE (1988–present) (search terms: ‘Burnout’ AND ‘Emergency Medicine’ AND ‘Physicians’; ‘Mental Stress’ AND ‘Emergency Medicine’ AND ‘Physicians’) was performed. The authors focused on articles that assessed burnout among emergency medicine physicians. Most studies used the Maslach Burnout Inventory to quantify burnout, allowing for cross‐study (and cross‐country) comparisons. Emergency medicine has burnout levels in excess of 60% compared with physicians in general (38%). Despite this, most emergency medicine physicians (>60%) are satisfied with their jobs. Both work‐related (hours of work, years of practice, professional development activities, non‐clinical duties etc.) and non‐work‐related factors (age, sex, lifestyle factors etc.) are associated with burnout. Despite the heavy burnout rates among emergency medicine physicians, little work has been performed in this field. Factors responsible for burnout among various emergency medicine populations should be determined, and appropriate interventions designed to reduce burnout.

Polymethylmethacrylate bone cements and additives: A review of the literature

Polymethylmethacrylate (PMMA) bone cement technology has progressed from industrial Plexiglass administration in the 1950s to the recent advent of nanoparticle additives. Additives have been trialed to address problems with modern bone cements such as the loosening of prosthesis, high post-operative infection rates, and inflammatory reduction in interface integrity. This review aims to assess current additives used in PMMA bone cements and offer an insight regarding future directions for this biomaterial. Low index (< 15%) vitamin E and low index (< 5 g) antibiotic impregnated additives significantly address infection and inflammatory problems, with only modest reductions in mechanical strength. Chitosan (15% w/w PMMA) and silver (1% w/w PMMA) nanoparticles have strong antibacterial activity with no significant reduction in mechanical strength. Future work on PMMA bone cements should focus on trialing combinations of these additives as this may enhance favourable properties.

Burnout in orthopaedic surgeons: a review

Training and practice of orthopaedic surgery are stressful endeavours, placing orthopaedic surgeons at risk of burnout. Burnout syndrome is associated with negative outcomes for patients, institutions and, especially, the surgeon. The aim of this review is to summarize available literature on burnout among orthopaedic surgeons and provide recommendations for future work in this field.

Prevalence and factors of burnout among Australian orthopaedic trainees: a cross-sectional study.

Purpose. To assess the prevalence and factors of burnout among Australian orthopaedic trainees. Methods. 236 orthopaedic registrars of the Australian Orthopaedic Association were invited to participate in a 32-item survey by email. The questionnaire assessed potential factors associated with burnout, satisfaction with the choice of orthopaedics as a career and work-life balance, and subjective overall health, as well as 3 subscales of the Maslach Burnout Inventory – Human Services Survey for assessing burnout: emotional exhaustion, depersonalisation, and personal accomplishment. Participants with high levels of either emotional exhaustion or depersonalisation were defined as having burnout. Those with and without burnout were compared. Results. 51 (22%) of the 236 trainees completed the questionnaire. Of whom, 88% were satisfied with their choice of orthopaedics as a career, whereas 27% were satisfied with their work-life balance. 27 (53%) respondents were considered burned out. Compared with those who did not burn out, those who burned out were less satisfied with their careers (p=0.004) and work-life balance (p=0.021). Conclusion. 53% of Australian orthopaedic trainees were burned out. Burnout trainees were more likely to be dissatisfied with their career choice and work-life balance. Active interventions to combat burnout and improve work-life balance are needed.

Bone morphogenetic protein-7: review of signalling and efficacy in fracture healing

Summary Bone morphogenetic proteins (BMPs) are a group of signalling molecules that belong to the transforming growth factor-β superfamily of proteins. Initially identified for their ability to induce bone formation, recent advances in the understanding of cellular and molecular mechanisms regarding BMPs have led to the use of the growth factor to accelerate bone healing. Recent clinical trials have demonstrated that BMPs, BMP-7 in particular, may present an alternative line of treatment other than the gold standard, autogenous bone grafting, in the treatment of fracture nonunion. We performed a literature search in September 2014 of PubMed and Embase using search terms, including “bone morphogenetic proteins”, “BMP-7”, “non-union”, “fracture healing” and “cost-effectiveness”, reviewing the efficacy, safety, and cost of treatment of nonunions with BMP-7. The authors further canvassed the reference lists of selected articles and used online search tools, such as Google Scholar. BMP-7 uses both the canonical and noncanonical signalling pathways. The treatment of fracture nonunion with recombinant human BMP-7 (rhBMP-7) has a comparable efficacy with that of autogenous bone grafting with an average union rate of 87% compared with 93% for bone grafting. Furthermore, fewer complications have been described with the use of rhBMP-7 compared with traditional bone grafting. We describe the signalling pathways that BMP-7 uses to exert its effect on bone. In nonunions, rhBMP-7 has been shown to have a similar efficacy to bone grafting with fewer complications.

Are Fast-Bowlers Prone to Back Injuries? Prevalence of Lumbar Spine Injuries in Fast-Bowlers: Review of MRI-Based Studies.

Background: Fast-bowlers in cricket subject their spines to repetitive stress. Objectives: The aim of this study was to review the prevalence of lumbar spine injuries among fast-bowlers. Materials and Methods: Medline and embase searches were performed. Further, the authors canvassed the reference list of available articles and used other search engines such as Google Scholar to identify a total of nine studies. Results: The prevalence of lumbar disc degeneration in fast-bowlers ranges from 21-65% with an incidence rate of 15% per year, and the prevalence of lumbar spine bony abnormalities ranges from 24-81%. Factors associated with lumbar spine injury in fast-bowlers are classified into un-modifiable (age) and modifiable (more intense bowling workload and mixed-bowling technique). Conclusions: Fast-bowlers have a high prevalence of lumbar spine injuries. Appropriate interventions, such as educational sessions, may be able to modify risk factors such as bowling workload and bowling technique and thus reduce injury prevalence.

Optimal parameters to avoid thermal necrosis during bone drilling: A finite element analysis

The drilling bone may potentially cause excessive frictional heat, which can lead to local bone necrosis. This heat generation and local necrosis has been suggested to contribute to the resorption of bone around the placed screws, ending in loss of screw purchase in the bone and inadvertent loosening and/or the bone‐implant construct. In vivo studies on this subject have inherent obstacles not the least of which is controlling the variables and real time bone temperature data acquisition. Theoretical models can be generated using computer software and the inclusion of known constants for the mechanical properties of metal and bone. These known Data points for the variables (drill bit and bone) enables finite element analysis of various bone drilling scenarios. An elastic–plastic three‐dimensional (3D) acetabular bone mode was developed and finite element model analysis (FEA) was applied to various simulated drilling procedures. The FEA results clearly indicate that the depth of drilling and the drill speed both have a significant effect on the temperature during drilling procedures. The reduction of the feeding speed leads to a reduction in bone temperature. Our data suggests that reducing the feeding speed regardless of RPMs and pressure applied could be a simple useful and effective way to reduce drilling temperatures. This study is the first step in helping any surgeon who drills bone and places screws to better understand the ideal pressure to apply and drill speed to employ and advance rate to avoid osteonecrosis.

O3DC: What We Can Do, What We Cannot Do and What We Need

Today with the challenges in orthopaedics, we need to create a bridge between orthopaedists and many scientists in many fields to produce a new strategy of education using 3D simulation. In this article, we will explain the aim of our platform (O3DC), in order to mention the viewpoints of our teamwork.

Bone marrow edema syndrome of the hip: an update on current concepts

Bone marrow edema syndrome of the hip is a rare condition that presents with self-limiting functional disability disproportionate to pain and signal changes on MRI consistent with bone marrow edema. Its etiology has not been established, but the most convincing theory implicates venous outflow obstruction from the diseased segment of bone. Bone marrow edema syndrome is a diagnosis of exclusion, following comprehensive work-up to rule out similarly presenting lesions. Once a diagnosis has been made a number of treatment strategies have been proposed, all with limited evidence. Conservative management is only supportive and involves analgesia and restricted weight bearing. Medical management with bisphosphonates and iloprost yield satisfactory results with minimal adverse effects. Alternative therapies include extracorporeal shock wave and hyperbaric oxygen therapy. Surgical core decompression offers immediate pain relief and faster recovery but may only be offered for severe, refractory disease.