Does topical vancomycin prevent fracture-related infections in closed fractures undergoing open reduction and internal fixation? A randomised controlled trial.

PURPOSE: The role of topical vancomycin in fracture-related infection (FRI) is debatable. Very few studies have reported their efficacy in open and high-risk extremity fractures. This study aimed to assess topical vancomycin's role in reducing FRI in closed fractures undergoing open surgical intervention with an implant. METHODS: This prospective randomized cohort study was carried out between February 2021 to January 2022. Patients with isolated closed fractures, who were planned for open reduction and internal fixation within 2 weeks from the time of injury were included for this study. The data collected included age, gender, socioeconomic status, mechanism of injury, diagnosis, Tscherne classification, and time interval to take up for surgery. Patients were randomized into the intervention and control groups using the block randomization technique. The control group received only systemic antibiotic prophylaxis, whereas the intervention group received topical application of vancomycin powder in the surgical wound alongside systemic antibiotic prophylaxis. The primary outcome measure was the incidence of FRI among these individuals. Clinical and radiological findings and culture reports (in cases with infection) were recorded during the post-operative period and at 6 weeks of follow-up. All relevant statistical calculations were done using STATA statistical/data analysis-parallel edition version 16.0 (StataCorp LLC). The quantitative variables like age and duration of the surgery were assessed for normalcy by Shapiro-Wilk W test. An independent samples t-test with equal variances was applied to the age data. Fisher's exact test was used for the analysis of the primary outcome measure (presence of FRI following surgery), and "Risk of FRI" and "Risk difference" between the 2 groups was calculated. The strength of the association between qualitative variables was assessed using the Fisher's exact and Chi-square tests, respectively. RESULTS: There were 88 patients included in this study. No statistical significance was found about FRI between both groups (p = 0.494). At 6 weeks following surgery, no incidence of infection was observed in the intervention group. Two infections (4.5%) were found in the control group, with positive cultures reported in one of them but none in the treatment group. Radiologically, 15.9% of patients in the control group showed lysis around the implant compared to 2.3% in the intervention group. Impaired fracture healing was observed in 22.7% of patients in the intervention group compared to 15.9% in the control group. CONCLUSION: Applying topical vancomycin in closed fractures undergoing open reduction and internal fixation does not significantly reduce the incidence of FRI until the end of 6 weeks following surgery.

A phase 1 study to assess the pharmacokinetics, safety, and tolerability of fremanezumab doses (225 mg, 675 mg and 900 mg) in Japanese and Caucasian healthy subjects.

OBJECTIVES: The primary and secondary objectives of this phase 1 study were to evaluate the pharmacokinetic profile, safety, and immunogenicity of fremanezumab subcutaneous (sc) doses tested in phase 2 and 3 trials (225 mg, 675 mg and 900 mg) following single administration in Japanese (n = 32) and Caucasian (n = 32) healthy subjects. METHODS: Japanese and matched Caucasian healthy subjects were enrolled into one of four cohorts and were randomly assigned to one of four treatments: 225, 675, or 900 mg fremanezumab, or placebo. Pharmacokinetic and immunogenicity sampling, and safety and tolerability assessments occurred at one inpatient visit and 12 ambulatory visits during the 36-week study. RESULTS: Pharmacokinetic analyses included those randomized to fremanezumab (n = 24 for each ethnic group) and safety analyses included all subjects enrolled in the study (n = 32 for each ethnic group). Fremanezumab concentration-time profiles and pharmacokinetic parameters per dose were similar for Japanese and Caucasians at all dose levels. Geometric mean ratios (GMRs) for Cmax for Japanese to Caucasian subjects were 0.91, 1.04 and 1.14 for the 225 mg, 675 mg and 900 mg fremanezumab doses. GMRs for AUC0-inf were 0.96, 1.09, and 0.98, respectively. Median Tmax (range 5-11 days) and mean half-lives (range 31-39 days) were similar across doses for both ethnicities. Most frequently occurring adverse events were injection site reactions, abdominal pain, headache, upper respiratory tract infection, constipation and nasopharyngitis. There was no development of anti-drug-antibodies and no clinically meaningful changes in laboratory findings. CONCLUSION: The results of the pharmacokinetic exposure parameters and safety measures were similar for Japanese and Caucasians and support the once monthly and once quarterly sc injections of fremanezumab.

Evaluation of the effect of naproxen on the pharmacokinetics and pharmacodynamics of apixaban.

AIM: To assess pharmacokinetic and pharmacodynamic interactions between naproxen (a non-steroidal anti-inflammatory drug) and apixaban (an oral, selective, direct factor-Xa inhibitor). METHOD: In this randomized, three period, two sequence study, 21 healthy subjects received a single oral dose of apixaban 10 mg, naproxen 500 mg or co-administration of both. Blood samples were collected for determination of apixaban and naproxen pharmacokinetics and pharmacodynamics (anti-Xa activity, international normalized ratio [INR] and arachidonic acid-induced platelet aggregation [AAI-PA]). Adverse events, bleeding time and routine safety assessments were also evaluated. RESULTS: Apixaban had no effect on naproxen pharmacokinetics. However, following co-administration, apixaban AUC(0,∞), AUC(0,t) and Cmax were 54% (geometric mean ratio 1.537; 90% confidence interval (CI) 1.394, 1.694), 55% (1.549; 90% CI 1.400, 1.713) and 61% (1.611; 90% CI 1.417, 1.831) higher, respectively. Mean (standard deviation [SD]) anti-Xa activity at 3 h post-dose was approximately 60% higher following co-administration compared with apixaban alone, 4.4 [1.0] vs. 2.7 [0.7] IU ml(-1) , consistent with the apixaban concentration increase following co-administration. INR was within the normal reference range after all treatments. AAI-PA was reduced by approximately 80% with naproxen. Co-administration had no impact beyond that of naproxen. Mean [SD] bleeding time was higher following co-administration (9.1 [4.1] min) compared with either agent alone (5.8 [2.3] and 6.9 [2.6] min for apixaban and naproxen, respectively). CONCLUSION: Co-administration of naproxen with apixaban results in higher apixaban exposure and appears to occur through increased apixaban bioavailability. The effects on anti-Xa activity, INR and inhibition of AAI-PA observed in this study were consistent with the individual pharmacologic effects of apixaban and naproxen.

Opposition to Haryana government's medical education directive: not just about the fee hike.

A recent directive of the Haryana government has linked the MBBS course offered by the state government medical colleges to an annual bond of Rs 10 lakh. This move has been opposed by medical aspirants, medical students, as well as the medical association as it will further reduce avenues for affordable medical education. While this is indeed a grave concern, there is more that needs to be considered.

Repurposing Therapeutics for Potential Treatment of SARS-CoV-2: A Review.

The need for proven disease-specific treatments for the novel pandemic coronavirus SARS-CoV-2 necessitates a worldwide search for therapeutic options. Since the SARS-CoV-2 virus shares extensive homology with SARS-CoV and MERS-CoV, effective therapies for SARS-CoV and MERS-CoV may also have therapeutic potential for the current COVID-19 outbreak. To identify therapeutics that might be repositioned for treatment of the SARS-CoV-2 disease COVID-19, we strategically reviewed the literature to identify existing therapeutics with evidence of efficacy for the treatment of the three coronaviruses that cause severe respiratory illness (SARS-CoV, MERS-CoV, and SARS-CoV-2). Mechanistic and in vitro analyses suggest multiple promising therapeutic options with potential for repurposing to treat patients with COVID-19. Therapeutics with particularly high potential efficacy for repurposing include camostat mesylate, remdesivir, favipiravir, tocilizumab, baricitinib, convalescent plasma, and humanized monoclonal antibodies. Camostat mesylate has shown therapeutic potential, likely by preventing viral entry into epithelial cells. In early research, the targeted antivirals remdesivir and favipiravir appear to benefit patients by decreasing viral replication; clinical trials suggest that remdesivir speeds recovery from COVID-19. Tocilizumab and baricitinib appear to improve mortality by preventing a severe cytokine storm. Convalescent plasma and humanized monoclonal antibodies offer passive immunity and decreased recovery time. This review highlights potential therapeutic options that may be repurposed to treat COVID-19 and suggests opportunities for further research.

Can Intensified Tuberculosis Case Finding Efforts at Nutrition Rehabilitation Centers Lead to Pediatric Case Detection in Bihar, India?

INTRODUCTION: Seven district-level Nutritional Rehabilitation Centres (NRCs) in Bihar, India provide clinical and nutritional care for children with severe acute malnutrition (SAM). AIM: To assess whether intensified case finding (ICF) strategies at NRCs can lead to pediatric case detection among SAM children and link them to TB treatment under the Revised National Tuberculosis Control Programme (RNTCP). MATERIALS AND METHODS: A retrospective cohort study was conducted that included medical record reviews of SAM children registered for TB screening and RNTCP care during July-December 2012. RESULTS: Among 440 SAM children screened, 39 (8.8%) were diagnosed with TB. Among these, 34 (87%) initiated TB treatment and 18 (53%) were registered with the RNTCP. Of 16 children not registered under the RNTCP, nine (56%) weighed below six kilograms-the current weight requirement for receiving drugs under RNTCP. CONCLUSION: ICF approaches are feasible at NRCs; however, screening for TB entails diagnostic challenges, especially among SAM children. However, only half of the children diagnosed with TB were treated by the RNTCP. More effort is needed to link this vulnerable population to TB services in addition to introducing child-friendly drug formulations for covering children weighing less than six kilograms.

Beneficial and Adverse Effects of an LXR Agonist on Human Lipid and Lipoprotein Metabolism and Circulating Neutrophils.

The development of LXR agonists for the treatment of coronary artery disease has been challenged by undesirable properties in animal models. Here we show the effects of an LXR agonist on lipid and lipoprotein metabolism and neutrophils in human subjects. BMS-852927, a novel LXRß-selective compound, had favorable profiles in animal models with a wide therapeutic index in cynomolgus monkeys and mice. In healthy subjects and hypercholesterolemic patients, reverse cholesterol transport pathways were induced similarly to that in animal models. However, increased plasma and hepatic TG, plasma LDL-C, apoB, apoE, and CETP and decreased circulating neutrophils were also evident. Furthermore, similar increases in LDL-C were observed in normocholesterolemic subjects and statin-treated patients. The primate model markedly underestimated human lipogenic responses and did not predict human neutrophil effects. These studies demonstrate both beneficial and adverse LXR agonist clinical responses and emphasize the importance of further translational research in this area.

Identification and functional characterization of a Na(+)-independent large neutral amino acid transporter (LAT2) on ARPE-19 cells.

The objective of this study was to investigate the presence of a large neutral amino acid transporter on the ARPE-19 cell line. ARPE-19 cells were grown on 24-well plates for uptake studies. Uptake characteristics of [3H]L-phenylalanine (L-Phe) were determined at various concentrations and pH at 37 degrees C. Inhibition studies were conducted in presence of L- and D-amino acids, metabolic inhibitors, like ouabain, sodium azide, and in presence of sodium-free medium, to delineate the mechanism of uptake. RT-PCR was carried out on total RNA isolated from the ARPE-19 cells. Presence of Na(+)-free buffer did reduce the uptake rate. Hence, all experiments were carried out in Na(+)-free medium to delineate the sodium-independent uptake mechanism. Uptake of L-Phe on ARPE cells was found to be saturable with a Km = 89.35 +/- 14 microM, Vmax = 58.9 +/- 2.5 pmol min(-1) mg protein(-1), and Kd = 0.108 +/- 0.04 microl min(-1) mg protein(-1). Dose-dependent inhibition was observed with increasing concentrations of unlabeled L-Phe. Uptake also was found to be energy independent. Significant inhibition of [3H]L-Phe was observed with large neutral aromatic and aliphatic amino acids as well as small neutral amino acids. System L-specific inhibitor BCH produced partial inhibition of uptake. Neither acidic nor basic amino acids altered the uptake rate. Results obtained were predominantly characteristic of LAT2, particularly with respect to substrate selectivity and pH dependence. Bands for LAT2 were detected by RT-PCR in the ARPE cell line. This study provides biochemical evidence of the presence of a Na(+)-independent, facilitative transport system, LAT2, on the ARPE-19 cells.

Effect of P-glycoprotein on the ocular disposition of a model substrate, quinidine.

PURPOSE: The objective of this study was to determine the effect of the multi-drug efflux transport protein, P-glycoprotein (P-gp), on the ocular distribution of a model substrate, quinidine. METHODS: Male New Zealand albino rabbits (2-2.5 kg) were employed in these studies. Animals were kept under anesthesia and a concentric microdialysis probe was implanted in the vitreous humor and a linear probe in the anterior chamber. Isotonic phosphate buffered saline was perfused through the probes, and samples were collected every 20 minutes over a period of 10 hours. Quinidine was administered both systemically (5 mg/kg bodyweight) and intravitreally (5.68 microg and 0.568 microg). Inhibition experiments were performed in vivo in the presence of verapamil, which is a known P-gp inhibitor. RESULTS: Vitreal pharmacokinetic parameters of quinidine in the presence of verapamil, i.e., Area under the curve (AUC) (39.27 +/- 6.47 min. microg/ml), maximum concentration achieved (Cmax) (0.095 +/- 0.011 microg/ml), vitreal elimination half-life (231.96 +/- 10.77 min), vitreal permeation half-life (16.57 +/- 6.96 min) were significantly different from the control values (19.21 +/- 3.73 min. microg/ml, 0.05 +/- 0.008 microg/ml, 165.08 +/- 31.5 min, 43.29 +/- 12.5 min respectively). A significant elevation in anterior chamber Cmax and AUC was also observed in the presence of verapamil. Verapamil had no significant effect on vitreal kinetics of quinidine following intravitreal dose of 5.68 micro g, but a significant difference was observed at a lower dose of quinidine (0.568 microg). A decrease in vitreal elimination half-life and AUC was observed in the presence of verapamil relative to control. Ocular kinetics of fluorescein was studied to ascertain ocular barrier integrity in the presence of verapamil. Western-blot analysis of retina-choroid sections indicates expression of P-gp on rabbit retina-choroid. CONCLUSION: Results suggest the involvement of a multi drug efflux transporter on the retinal pigment epithelium and neural retina affecting the intraocular kinetics of its substrates following systemic and intravitreal administrations.

Sputum smear microscopy at two months into continuation-phase: should it be done in all patients with sputum smear-positive tuberculosis?

BACKGROUND: The Revised National Tuberculosis Control Program (RNTCP) of India recommends follow-up sputum smear examination at two months into the continuation phase of treatment. The main intent of this (mid-CP) follow-up is to detect patients not responding to treatment around two-three months earlier than at the end of the treatment. However, the utility of mid-CP follow-up under programmatic conditions has been questioned. We undertook a multi-district study to determine if mid-CP follow-up is able to detect cases of treatment failures early among all types of patients with sputum smear-positive TB. METHODOLOGY: We reviewed existing records of patients with sputum smear-positive TB registered under the RNTCP in 43 districts across three states of India during a three month period in 2009. We estimated proportions of patients that could be detected as a case of treatment failure early, and assessed the impact of various policy options on laboratory workload and number needed to test to detect one case of treatment failure early. RESULTS: Of 10055 cases, mid-CP follow-up was done in 6944 (69%) cases. Mid-CP follow-up could benefit 117/8015 (1.5%) new and 206/2040 (10%) previously-treated sputum smear-positive cases by detecting their treatment failure early. Under the current policy, 31 patients had to be tested to detect one case of treatment failure early. All cases of treatment failure would still be detected early if mid-CP follow-up were discontinued for new sputum smear-positive cases who become sputum smear-negative after the intensive-phase of treatment. This would reduce the related laboratory workload by 69% and only 10 patients would need to be tested to detect one case of treatment failure early. CONCLUSION: Discontinuation of mid-CP follow-up among new sputum smear-positive cases who become sputum smear-negative after completing the intensive-phase of treatment will reduce the laboratory workload without impacting overall early detection of cases of treatment failure.

Transport of HIV-protease inhibitors across 1 alpha,25di-hydroxy vitamin D3-treated Calu-3 cell monolayers: modulation of P-glycoprotein activity.

PURPOSE: The presence of P-glycoprotein (P-gp) within the lipid bi-layers of the absorptive cells greatly influences drug entry into the HIV-infected sanctuary sites. The objective of this study was to acces the potential role of pulmonary cells expressing high levels of P-gp in the efflux of potent anti-HIV drugs such as protease inhibitors. METHODS: Human airway epithelium-derived Calu-3 cells grown in the presence of 0.025 mM 1alpha,25di-hydroxy Vitamin D3 (di-OH vit D3) were used as a model to evaluate the effects of p-glycoprotein efflux of HIV protease inhibitors. Cells used as controls were not treated with di-OH vit D3. The anti-HIV agents 3H Ritonavir and Saquinavir (50 microM) were used as model compounds for influx and efflux studies RESULTS: Di-OH vit D3 treatment enhanced the differentiation c Calu-3 cells indicated by more cilia and mucus secretion. It also caused elevated P-gp expression as demonstrated by Western Bla analysis and enhanced basal to apical transport of cyclosporine as compared with untreated cells. The amount of Saquinavir transported, after 3 h, across untreated Calu-3 cells (A-B) was 3-fold higher (1.62 microg; Papp = 2A (+/- 0.79) x 10(-6) cm/s) than di-OH vi D3-treated cells (0.57 microg with the Papp = 5.02 (+/- 0.62) x 10(-7) cm/s) Similar transport profiles were obtained for 3H ritonavir and a significant increase (p < 0.05) in the A-B transport (2.5-fold) of 3H ritonavir was observed when the cell monolayers were preincubated with testosterone prior to transport studies. However, transport of AZT remained unaltered in di-OH vit D3 treated monolayers. CONCLUSION: Modulation of P-gp activity may be necessary to increase the therapeutic efficacy of protease inhibitors against HIV-1 reservoirs across alveolar lining cells and fluids.