Topical Vancomycin Powder and Dilute Povidone-Iodine Lavage Reduce the Rate of Early Periprosthetic Joint Infection After Primary Total Knee Arthroplasty

BackgroundVancomycin powder and dilute povidone-iodine lavage (VIP) was introduced to reduce the incidence of periprosthetic joint infection (PJI) in high-risk total knee arthroplasty (TKA) patients. We hypothesize that VIP can reduce the incidence of early PJI in all primary TKA patients, regardless of preoperative risk.MethodsAn infection database of primary TKAs performed before a VIP protocol was implemented (January 2012-December 2013), during a time when only high-risk TKAs received VIP (January 2014-December 2015), and when all TKAs received VIP (January 2016-September 2019) at an urban, university-affiliated, not-for-profit orthopedic hospital was retrospectively reviewed to identify patients with PJI. Criteria used for diagnosis of PJI were the National Healthcare Safety Network and Musculoskeletal Infection Society guidelines.ResultsVIP reduced early primary TKA PJI incidence in both the high-risk and all-risk cohorts compared with the pre-VIP cohort by 44.6% and 56.4%, respectively (1.01% vs 0.56% vs 0.44%, P = .0088). In addition, after introducing VIP to all-risk TKA patients, compared with high-risk TKA patients, the relative risk of PJI dropped an additional 21.4%, but this finding did not reach statistical significance (0.56% vs 0.44%, P = .4212). There were no demographic differences between the 3 VIP PJI cohorts.ConclusionVIP is associated with a reduced early PJI incidence after primary TKA, regardless of preoperative risk. With the literature supporting its safety and cost-effectiveness, VIP is a value-based intervention, but given the nature of this historical cohort study, a multicenter randomized controlled trial is underway to definitively confirm its efficacy.     

Protection From the Second Warm Ischemic Injury in Kidney Transplantation Using an Ex Vivo Porcine Model and Thermally Insulating Jackets

BackgroundKidney transplantation is the optimum treatment for kidney failure in carefully selected patients. Technical surgical complications and second warm ischemic time (SWIT) increase the risk of delayed graft function (DGF) and subsequent short- and long-term graft outcomes including the need for post-transplant dialysis and graft failure. Intraoperative organ thermal regulation could reduce SWIT, minimizing surgical complications due to time pressure, and limiting graft ischemia-reperfusion injury.MethodsA novel ischemic-injury thermal protection jacket (iiPJ) was designed and fabricated in silicone composite and polyurethane (PU) elastomer prototypes. Both were compared with no thermal insulation as controls. Time to reach ischemic threshold (15°C) and thermal energy transfer were compared. A water bath model was used to examine the thermal protective properties of porcine kidneys, as a feasibility study prior to in vivo translation.ResultsIn both iterations of the iiPJ, the time taken to reach the warm ischemia threshold was 35.2 ± 1.4 minutes (silicone) and 38.4 ± 3.1 minutes (PU), compared with 17.2 ± 1.5 minutes for controls (n = 5, P < .001 for both comparisons). Thermal energy transfer was also found to be significantly less for both iiPJ variants compared with controls. There was no significant difference between the thermal performance of the 2 iiPJ variants.ConclusionProtection from SWIT by using a protective insulation jacket is feasible. With clinical translation, this novel strategy could facilitate more optimal surgical performance and reduce transplanted organ ischemia-reperfusion injury, in particular the SWIT, potentially affecting delayed graft function and long-term outcomes.     

Endogenous circulating DNA in systemic lupus erythematosus. Occurrence as multimeric complexes bound to histone.

Little is known about endogenous systemic lupus erythematosus (SLE) plasma DNA even though it is the presumed precursor of DNA-containing immune complexes, thought to play a central role in lupus glomerulonephritis. DNA purified from SLE plasma formed discrete bands, corresponding to sizes of about 150-200, 400, 600, and 800 bp, closely resembling the characteristic 200 bp "ladder" found with oligonucleosomal (ON) DNA. By radiolabeling DNA while in whole plasma, the very small amounts present could be further characterized. All of 24 such specimens formed two or more discrete bands on 6% PAGE. Detergent treatment of plasma resulted in a DNA migration pattern similar to that of purified DNA, suggesting disruption of DNA-protein complexes. DNA purified from authentic ON and detergent-treated ON behaved similarly. A significant portion of DNA, labeled in SLE plasma could be specifically immunoprecipitated with monoclonal antihistone antibody as was the case with ON. These immunoprecipitates, when redissolved, exhibited the expected size distribution upon PAGE. It is concluded that DNA in SLE plasma occurs as a series of multimeric complexes, at least a portion of which is noncovalently bound to histone. These results are consistent with an ON-like structure for SLE plasma DNA as had been suggested by theoretical considerations and may have important implications for its immunologic behavior in SLE and perhaps other disorders.     

The Influence of Site of Care on the Content of Prenatal Care for Low-Income Women

Objective: To assess whether site of prenatal care influences the content of prenatal care for low-income women. Design: Bivariate and logistic analyses of prenatal care content for low-income women provided at five different types of care sites (private offices, HMOs, publicly funded clinics, hospital clinics, and other sites of care), controlling for sociodemographic, behavioral, and maternal health characteristics. Participants: A sample of 3405 low-income women selected from a nationally representative sample of 9953 women surveyed by the National Maternal and Infant Health Survey, who had singleton live births in 1988, had some prenatal care (PNC), Medicaid participation, or a family income less than $12,000/year. Outcome Measures: Maternal report of seven initial PNC procedures (individually and combined), six areas of PNC advice (individually and combined), and participation in the Women Infant Children (WIC) nutrition program. Results: The content of PNC provided for low-income women does not meet the recommendations of the U.S. Public Health Service, and varies by site of delivery. Low-income women in publicly funded clinics (health departments and community health centers) report receiving more total initial PNC procedures and total PNC advice and have greater participation in the WIC program than similar women receiving PNC in private offices. Conclusions: Publicly funded sites of care appear to provide more comprehensive prenatal care services than private office settings. Health care systems reforms which assume equality of care across all sites, or which limit services to restricted sites, may foster unequal access to comprehensive PNC.     

Catecholamine modulatory effects of nepicastat (RS-25560-197), a novel,potent and selective inhibitor of dopamine-β-hydroxylase

1. Inhibitory modulation of sympathetic nerve function may have a favourable impact on the progression of congestive heart failure. Nepicastat is a novel inhibitor of dopamine-β-hydroxylase, the enzyme which catalyses the conversion of dopamine to noradrenaline in sympathetic nerves. The in vitro pharmacology and in vivo catecholamine modulatory effects of nepicastat were investigated in the present study.
2. Nepicastat produced concentration-dependent inhibition of bovine (IC₅₀=8.5±0.8 nM) and human (IC₅₀=9.0±0.8  nM)dopamine-β-hydroxylase. The corresponding R-enantiomer (RS-25560-198) was approximately 2–3 fold less potent than nepicastat. Nepicastat had negligible affinity (>10 μM) for twelve other enzymes and thirteen neurotransmitter receptors.
3. Administration of nepicastat to spontaneously hypertensive rats (SHRs) (three consecutive doses of either 3, 10, 30 or 100 mg kg⁻¹, p.o.; 12 h apart) or beagle dogs (0.05, 0.5, 1.5 or 5 mg kg⁻¹, p.o.; b.i.d., for 5 days) produced dose-dependent decreases in noradrenaline content, increases in dopamine content and increases in dopamine/noradrenaline ratio in the artery (mesenteric or renal), left ventricle and cerebral cortex. At the highest dose studied, the decreases in tissue noradrenaline were 47%, 35% and 42% (in SHRs) and 88%, 91% and 96% (in dogs) in the artery, left ventricle and cerebral cortex, respectively. When tested at 30 mg kg⁻¹, p.o., in SHRs, nepicastat produced significantly greater changes in noradrenaline and dopamine content, as compared to the R-enantiomer (RS-25560-198), in the mesenteric artery and left ventricle.
4. Administration of nepicastat (2 mg kg⁻¹, b.i.d, p.o.) to beagle dogs for 15 days produced significant decreases in plasma concentrations of noradrenaline and increases in plasma concentrations of dopamine and dopamine/noradrenaline ratio. The peak reduction (52%) in plasma concentration of noradrenaline and the peak increase (646%) in plasma concentration of dopamine were observed on day-6 and day-7 of dosing, respectively.
5. The findings of this study suggest that nepicastat is a potent, selective and orally active inhibitor of dopamine-β-hydroxylase which produces gradual modulation of the sympathetic nervous system by inhibiting the biosynthesis of noradrenaline. This drug may, therefore, be of value in the treatment of cardiovascular disorders associated with over-activation of the sympathetic nervous system, such as congestive heart failure.

     

Weekly Cisplatin induction chemotherapy in high-risk cervical-cancer patients with bulky tumor - a phase-ii study

In this study we evaluated efficacy and toxicity of a neoadjuvant chemotherapy regimen before radiation therapy or surgery in high-risk cevical cancer patients. Between January 1988 and July 1993, 37 out of 40 consecutive patients with bulky cervical carcinoma (>40 mm) received chemotherapy consisting of six (range 4-9) weekly courses of cisplatin (1 mg/kg), followed by radical surgery and/or radiotherapy. Thirty-six patients completed the planned sequence of treatment. Overall response rate was 65% after induction chemotherapy (complete 0% and partial 65%) and 73% (complete 57% and partial 16%) after definitive treatment. After a median follow-up of 23 (range 4-61) months the median duration of response was 29, 19 and 11 months for complete partial and non-responders respectively. Toxicities from induction chemotherapy were mild to moderate, reversible and tolerable and did not affect the subsequent application of the definitive treatment. The proposed cisplatin neoadjuvant chemotherapy regimen gave positive results in a good number of cases with low toxicity and without interfering with the definitive radio-surgical treatment of this group of high-risk patients. The number of cisplatin courses for best effect remains to be established.     

An Approach for Widening the Bioequivalence Acceptance Limits in the Case of Highly Variable Drugs

Purpose. Highly variable drugs pose a problem in bioequivalence assessment because they often fail to meet current regulatory acceptance criteria for average bioequivalence (80–125%). This paper examines alternative approaches to establishing bioequivalence. Methods. Suggested solutions have included alternate study designs, e.g., replicate and multiple dose studies, reducing the level of the confidence interval, and widening the acceptance limits. We focus on the latter approach. Results. A rationale is presented for defining wider acceptance limits for highly variable drugs. Two previously described methods are evaluated, and a new method having more desirable properties is proposed. Conclusions. We challenge the one size fits all current definition of bioequivalence acceptance limits for highly variable drugs, proposing alternative limits or goal posts which vary in accordance with the intrasubject variability of the reference product.