Pharmacokinetics of vindesine bolus and infusion

Summary The pharmacokinetics of vindesine were investigated during treatment of 15 patients with progressive malignancies refractory to conventional treatment. Patients were administered one of three IV dose schedules: 3.0 mg/m² bolus injection, 1.2 mg/m²/day infusion for 5 days, or 2.0 mg/m²/day infusion for 2 days. Concentrations of the drug in the serum and urine were determined by radioimmunoassay. Serum concentrations were highest (5×10^-7 M) in patients receiving a bolus injection, but fell to nondetectable levels by 48 h in four of five patients (terminal t_1/2 15.0±9.4 h). Compared with bolus injection, 1.2-to 1.4-fold greater areas under the blood concentration curve were observed during infusions of 2.0 mg/m² and 1.2 mg/m². Whereas steady-state concentrations (1×10^-8 M) were maintained throughout the infusion of 1.2 mg/m²/day progressively increasing serum levels were observed during the infusion of 2.0 mg/m²/day. Serum concentrations fell rapidly following discontinuation of the 2.0-mg/m² infusion, but were somewhat more sustained in the 1.2-mg/m² infusion group. The average urinary excretion was similar for each dose-schedule (8%–11% of the total dose). The pharmacokinetics of vindesine are influenced by variations in dose schedule.     

Human Diversity of Killer Cell Immunoglobulin-Like Receptors and Human Leukocyte Antigen Class I Alleles and Ebola Virus Disease Outcomes

We investigated the genetic profiles of killer cell immunoglobulin-like receptors (KIRs) in Ebola virus–infected patients. We studied the relationship between KIR–human leukocyte antigen (HLA) combinations and the clinical outcomes of patients with Ebola virus disease (EVD). We genotyped KIRs and HLA class I alleles using DNA from uninfected controls, EVD survivors, and persons who died of EVD. The activating 2DS4–003 and inhibitory 2DL5 genes were significantly more common among persons who died of EVD; 2DL2 was more common among survivors. We used logistic regression analysis and Bayesian modeling to identify 2DL2, 2DL5, 2DS4–003, HLA-B-Bw4-Thr, and HLA-B-Bw4-Ile as probably having a significant relationship with disease outcome. Our findings highlight the importance of innate immune response against Ebola virus and show the association between KIRs and the clinical outcome of EVD.     

Disaggregating proportional multistate lifetables by population heterogeneity to estimate intervention impacts on inequalities

The mortality pattern from birth to age five is known to vary by underlying cause of mortality, which has been documented in multiple instances. Many countries without high functioning vital registration systems could benefit from estimates of age- and cause-specific mortality to inform health programming, however, to date the causes of under-five death have only been described for broad age categories such as for neonates (0–27 days), infants (0–11 months), and children age 12–59 months. We adapt the log quadratic model to mortality patterns for children under five to all-cause child mortality and then to age- and cause-specific mortality (U5ACSM). We apply these methods to empirical sample registration system mortality data in China from 1996 to 2015. Based on these empirical data, we simulate probabilities of mortality in the case when the true relationships between age and mortality by cause are known. We estimate U5ACSM within 0.1–0.7 deaths per 1000 livebirths in hold out strata for life tables constructed from the China sample registration system, representing considerable improvement compared to an error of 1.2 per 1000 livebirths using a standard approach. This improved prediction error for U5ACSM is consistently demonstrated for all-cause as well as pneumonia- and injury-specific mortality. We also consistently identified cause-specific mortality patterns in simulated mortality scenarios. The log quadratic model is a significant improvement over the standard approach for deriving U5ACSM based on both simulation and empirical results.     

Is There an Association Between Negative Patient-Experience Comments and Perioperative Outcomes After Primary Total Hip Arthroplasty?

BackgroundMultiple stakeholders are interested in improving patient experience after primary total hip arthroplasty due to shifts toward patient-centered care. Patient free-text narratives are a potentially valuable but largely unexplored source of data.MethodsThe records of 383 patients who underwent primary total hip arthroplasty between August 2016 and August 2019 were combined with vendor-supplied patient satisfaction data, which included patient free-text comments and the Press Ganey satisfaction survey. A total of 1295 patient comments were analyzed for sentiment, and negative comments were categorized into nine themes. Postoperative outcomes, patient-reported outcome measures, and traditional measures of satisfaction were compared between patients who provided a negative comment vs those who did not. Multivariable regression was used to determine perioperative variables associated with providing a negative comment.ResultsOf the 1295 patient comments: 54% were positive, 24% were negative, 10% were mixed, and 12% were neutral. Top two themes of negative comments were room condition (25%) and inefficient communication (23%). There were no differences in studied outcomes (eg. peak pain intensity, length of stay, or improvements in hip injury and osteoarthritis outcome scores Jr. and pain visual analog scale scores at 6-week follow-up) between those who provided negative comments vs those who did not (P > .05). However, patients who made negative comments were less likely to recommend their hospital care to peers (P < .001). Finally, patients who had >2 allergies (P = .024) were more likely to provide negative comments.ConclusionThe present study demonstrates that patient satisfaction appears not to be a reliable sole proxy for traditional objective outcome measures of pain relief and functional improvement.     

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.     

Analysis of the influence of species,intervertebral disc height and Pfirrmann classification on failure load of an injured disc using a novel disc herniation model

Background ContextAnnular repair devices offer a solution to recurrent disc herniations by closing an annular defect and lowering the risk of reherniation. Given the significant risk of neurologic injury from device failure it is imperative that a reliable preclinical model exists to demonstrate a high load to failure for the disc repair devices.PurposeTo establish a preclinical model for disc herniation and demonstrate how changes in species, intervertebral disc height and Pfirrmann classification impacts failure load on an injured disc. We hypothesized that: (1) The force required for disc herniation would be variable across disc morphologies and species, and (2) for human discs the force to herniation would inversely correlate with the degree of disc degeneration.Study designAnimal and human cadaveric biomechanical model of disc herniation.MethodsWe tested calf lumbar spines, bovine tail segments and human lumbar spines. We first divided individual lumbar or tail segments to include the vertebral bodies and disc. We then hydrated the specimens by placing them in a saline bath overnight. A magnetic resonance images were acquired from human specimens and a Pfirrmann classification was made. A stab incision measuring 25% of the diameter of the disc was then done to each specimen along the posterior intervertebral disc space. Each specimen was placed in custom test fixtures on a servo-hydraulic test frame (MTS, Eden Prarie, MN) such that the superior body was attached to a 10,000 lb load cell and the inferior body was supported on the piston. A compressive ramping load was placed on the specimen in load control at 4 MPa/sec stopping at 75% of the disc height. Load was recorded throughout the test and failure load calculated. Once the test was completed each specimen was sliced through the center of the disc and photos were taken of the cut surface.ResultsFifteen each of calf, human, and bovine tail segments were tested. The failure load varied significantly between specimens (p<.001) with human specimens having the highest average failure load (8154±2049 N). Disc height was higher for lumbar/bovine tail segments as compared to calf specimens (p<.001) with bovine tails having the highest disc height (7.1±1.7 mm). Similarly, human lumbar discs had a cross sectional area that was greater than both bovine tail/calf lumbar spines (p<.001). There was no correlation between disc height and failure load within each individual species (p>.05). Cross sectional area and failure load did not correlate with failure load for human lumbar spine and bovine tails (p>.05) but did correlate with calf spine (r=0.53, p=.04). There was a statistically significant inverse correlation between disc height and Pfirrmann classification for human lumbar spines (r=?0.84, p<.001). There was also a statistically significant inverse relationship between Pfirrmann classification and failure load (r=?0.58, p=.02).ConclusionsWe have established a model for disc herniation and have shown how results of this model vary between species, disc morphology, and Pfirrmann classification. Both hypotheses were accepted: The force required for disc herniation was variable across species, and the force to herniation for human spines was inversely correlated with the degree of disc degeneration. We recommend that models using human intervertebral discs should include data on Pfirrmann classification, while biomechanical models using calf spines should report cross sectional area. Failure loads do not vary based on dimensions for bovine tails.Clinical SignificanceOur analysis of models for disc herniation will allow for quicker, reliable comparisons of failure forces required to induce a disc herniation. Future work with these models may facilitate rapid testing of devices to repair a torn/ruptured annulus.     

Neuroendocrine mechanisms that delay and initiate puberty in higher primates

This paper highlights a series of studies using the male rhesus monkey that has led to a model for the control of the onset of puberty in higher primates. The model proposes that the timing of puberty in these species is governed by the duration of a central brake that, during juvenile development, holds in check the hypothalamic network of gonadotropin-releasing hormone (GnRH) neurons, which, in the adult, drive the pituitary-gonadal axis. The neurobiology of this hypothalamic brake, and the physiological mechanisms that time its application and removal, are incompletely understood. Nevertheless, the pubertal resurgence of pulsatile GnRH release, which terminates the juvenile phase of primate development and triggers the initiation of puberty in man and monkeys, is associated with structural and molecular remodeling of the hypothalamus. A major component of this developmental plasticity appears to involve neuropeptide Y (NPY). NPY inhibits GnRH release, and NPY gene expression in the hypothalamus is elevated during juvenile development when GnRH release is restrained. Since the changes in hypothalamic function and morphology that trigger primate puberty unfold in the absence of gonadal steroid feedback, the possibility is raised that, in addition to activating the pituitary-gonadal axis at this stage of development, they may also contribute directly to the causation of behaviors and affective states that emerge at adolescence.     

Specific cerebellar reductions in children with chromosome 22q11.2 deletion syndrome

Children with chromosome 22q11.2 deletion syndrome commonly are found to have morphological brain changes, cognitive impairments, and elevated rates of psychopathology. One of the most commonly and consistently reported brain changes is reduced cerebellar volume. Here, we demonstrate that, in addition to the global cerebellum reductions previously reported, volumetric reductions of the anterior lobule and the vermal region of the neo-cerebellum in the mid-sagittal plane best differentiate children with the deletion from typically developing children. These results suggest that the morphological changes of specific portions of the cerebellum may be an important underlying substrate of cognitive impairments and increased incidence of psychopathology in this group.     

"Could it be asthma?": the impact of a mass media campaign aimed at raising awareness about asthma in Australia

Asthma is a very common chronic illness in Australia; however,unrecognized and undertreated asthma is responsible for muchpreventable morbidity in the community. In 1988, a coalitionof private and public sector agencies was formed to conducta national mass communications program aimed at increasing awarenessabout asthma. This pilot campaign comprised a mailout to allprimary care physicians and a mass media campaign, entitled"Could it be asthma?". The impact of this media-based strategywas assessed using population surveys of 1300 adults beforeand after the campaign. Following the campaign, recall of recentasthma media messages increased from 24 to 49% (P < 0.001)and the proportion who recognized possible asthma symptoms intheir household increased from 3.4 to 5.5% following the campaign.Of those with symptoms, twice as many reported that they visiteda doctor to have their symptoms assessed after the campaign.Knowledge of asthma symptoms was significantly higher followingthe campaign (P < 0.001), after adjustment for age, sex andthe presence of asthma in the respondents family. The campaignappeared to have some success in raising awareness about asthma,and has been followed by the development of a National AsthmaCampaign in Australia focusing on reducing asthma morbidityand improving its management.