Bias and variance reduction procedures in non-parametric regression

The purpose of this study is to determine the effect of three improvement methods on nonparametric kernel regression estimators. The improvement methods are applied to the Nadaraya-Watson estimator with cross-validation bandwidth selection, the Nadaraya-Watson estimator with plug-in bandwidth selection, the local linear estimator with plug-in bandwidth selection and a bias corrected nonparametric estimator proposed by Yao (2012), based on cross-validation bandwith selection. The performance of the different resulting estimators are evaluated by empirically calculating their mean integrated squared error (MISE), a global discrepancy measure. The first two improvement methods proposed in this study are based on bootstrap bagging and bootstrap bragging procedures, which were originally introduced and studied by Swanepoel (1988, 1990), and hereafter applied, e.g., by Breiman (1996) in machine learning. Bagging and bragging are primarily variance reduction tools. The third improvement method, referred to as boosting, aims to reduce the bias of an estimator and is based on a procedure originally proposed by Tukey (1977). The behaviour of the classical Nadaraya-Watson estimator with plug-in estimator turns out to be a new recommendable nonparametric regression estimator, since it is not only as precise and accurate as any of the other estimators, but it is also computationally much faster than any other nonparametric regression estimator considered in this study

Exposure of a 23F serotype strain of <i>Streptococcus pneumoniae</i> to cigarette smoke condensate is associated with selective upregulation of genes encoding the two-component regulatory system 11 (TCS11)

Alterations in whole genome expression profiles following exposure of the pneumococcus (strain 172, serotype 23F) to cigarette smoke condensate (160 μg/mL) for 15 and 60 min have been determined using the TIGR4 DNA microarray chip. Exposure to CSC resulted in the significant (P &#60; 0.014–0.0006) upregulation of the genes encoding the two-component regulatory system 11 (TCS11), consisting of the sensor kinase, hk11, and its cognate response regulator, rr11, in the setting of increased biofilm formation. These effects of cigarette smoke on the pneumococcus may contribute to colonization of the airways by this microbial pathogen

Hypertriglyceridaemia and the risk of pancreatitis six months post lopinavir/ritonavir initiation

Background: Hypertriglyceridaemia (HTG) is an important risk factor for pancreatitis and cardiovascular disease (CVD), depending on severity. Hypertriglyceridaemia is common in human immunodeficiency virus (HIV) infection and is also a common complication of lopinavir/ritonavir (LPV/r).Objectives: To evaluate the risk of pancreatitis associated with HTG in patients six months post initiation of LPV/r-based therapy in a regional public hospital.Methods: Triglyceride (TG), serum amylase (s-amylase) and CD4+ count values were retrospectively investigated six months post LPV/r-based initiation. Age, gender, previous antiretroviral regimen and period since HIV diagnosis were also recorded.Results: The final sample consisted of 194 patients, 50 males and 144 females; mean (± standard deviation [s.d.]) age was 39.52 (± 9.98) years, and the mean (± s.d.) period since HIV diagnosis was 91.32 (± 25.18) months. Normal TG levels (&lt; 1.70 mmol/L) were detected in only 55% of patients and the rest presented with some degree of HTG. The mean (± s.d.) TG for the entire sample was elevated at 1.94 (± 1.30) mmol/L with the mean (± s.d.) of the males at 2.36 (± 1.74) – statistically higher compared to the females at 1.79 (± 1.08) mmol/L (p = 0.034). No cases of pancreatitis were recorded and the time since HIV diagnosis did not indicate any statistically significant differences in the means of the TG, serum amylase or CD4 count values.Conclusion: Triglyceride levels were not substantially elevated to induce pancreatitis at six months post initiation of LPV/r, but were elevated above the accepted upper normal limit of 1.70 mmol/L which may have implications for cardiovascular risk

Comparison of adherence measures using claims data in the South African private health sector

Background. Medication adherence measurement is becoming increasingly important. Biological assays and markers, directly observed therapy, self-reports, pill counts and surveys have been successfully used to assess adherence under various circumstances, but may be limited by cost, ethical concerns and self-reported bias. Administrative claims data, in addition to offering a solution to these limitations, provide access to large study populations under real clinical practice situations, and in a timely and effective manner. With the wide range of adherence measures determined from claims data available – some of which have been found to be mathematically equivalent – researchers are often faced with the decision of choosing which is appropriate. An assessment of the various measures is therefore important for better understanding and to facilitate future adherence studies using administrative data.Objectives. To compare different adherence measures using data from a medicines claims database in South Africa (SA), employing montelukast for the purpose of illustration.Methods. This retrospective, cross-sectional research used data from 1 January 2006 to 31 December 2015 from a privately owned pharmaceutical benefits management (PBM) company in SA. Claims for montelukast were identified and adherence was determined using the continuous multiple-interval measure of oversupply (CMOS), compliance ratio (CR), modified medication possession ratio (MPRm), refill compliance rate (RCR), continuous single-interval measure of medication acquisition (CSA) and proportion of days covered (PDC) capped at 1. The measures were compared with the medication possession ratio (MPR) as the reference.Results. The MPR, CMOS and CR were equivalent, each yielding an adherence value of 86%. The MPRm, RCR and average CSA yielded higher adherence values of 96.9%, 117.2% and 129.0%, respectively, whereas the PDC produced a lower adherence value of 76.0%. The measures that used the entire study period as the denominator produced consistent results compared with the measures that used the difference between claims dates as denominator.Conclusions. The MPR is considered the most widely used metric to measure adherence using administrative data, but it may not always be applicable owing to the type of data available. Adherence computed using the CR, CMOS and PDC capped was found to be comparable to the MPR, and they may therefore be used as alternatives.

Acute changes in haematocrit leading to polycythaemia in late-onset hypogonadism patients that receive testosterone replacement therapy: a South African study

Background: According to the literature, parenteral testosterone replacement therapy (TRT)-induced polycythaemia is associated with cardiovascular events. No or minimal data exist for the prevalence of TRT-induced polycythaemia in lateonset hypogonadism (LOH) patients from South Africa. Polycythaemia is the side effect most frequently associated with parental TRT formulations.Design: This was a quantitative, observational, descriptive, retrospective study.Setting: The study setting was a private practice male clinic in Emalahleni.Subject: An all-inclusive sampling method was used.Outcome measures: The main outcome measure for polycythaemia was haematocrit (Hct). An Hct percentage of &gt; 50% at month 3 (post-treatment initiation) constituted a positive diagnosis for polycythaemia. For the rise in total testosterone (TT) and Hct, the variance was used as documented between pre- and post-treatment initiation.Results: The prevalence of polycythaemia was 34%. A statistically significant increase in both TT and Hct was observed. The Cohen’s d effect size was 0.68 and 0.73, respectively, for TT and Hct.Conclusion: Depot-testosterone undecanoate parenteral formulation induces polycythaemia in LOH patients, where the rise in TT demonstrates the effectiveness of therapy

Effect of antimicrobial peptides on planktonic growth, biofilm formation and biofilm-derived bacterial viability of Streptococcus pneumoniae

Streptococcus pneumoniae is a leading cause of pneumonia mortality globally. Pneumococcal disease is often associated with prolonged colonisation of hosts and this process is facilitated by biofilm formation that is largely resistant to conventional antibiotics. We investigated the effects of antimicrobial peptides (AMPs) lysozyme, lactoferrin, LL37 and a combination of all three on planktonic growth, biofilm formation and biofilm-derived bacterial viability by S. pneumoniae, serotype 23F. Planktonic growth and biofilm-derived bacterial viability were determined using standard colony-forming techniques, while biofilm formation was measured using a crystal violet based spectrophotometric method. Relative to controls, lysozyme significantly reduced biofilm formation (0.08 OD vs. 0.10 OD at 570 nm, p = 0.01), while LL37 and the AMP combination increased biofilm formation (0.14 OD vs. 0.10 OD at 570 nm, p = 0.01). The combination of AMPs significantly decreased planktonic growth (1.10 × 108 colony-forming units per millilitres [CFU/ mL] vs. 2.13 × 108 CFU/mL, p = 0.02). Biofilm-derived bacterial viability was greatly reduced by exposure to a combination of AMPs (1.05 × 105 CFU/mL vs. 1.12 × 106 CFU/mL, p = 3.60 × 10−8). Streptococcus pneumoniae displays marked resistance to the individual AMPs. A combination of lysozyme, lactoferrin and LL37 effectively inhibited planktonic growth and biofilm-derived bacterial viability; however, persister cell growth was still evident after exposure.The Medical Research Council (MRC) Unit for Inflammation and Immunity as well as the National Research Foundation (NRF).https://sajid.co.za/index.php/sajiddm2022Internal Medicin

Protein kinase C promotes restoration of calcium homeostasis to platelet activating factor-stimulated human neutrophils by inhibition of phospholipase C

<p>Abstract</p> <p>Background</p> <p>The role of protein kinase C (PKC) in regulating the activity of phospholipase C (PLC) in neutrophils activated with the chemoattractant, platelet-activating factor (PAF, 20 and 200 nM), was probed in the current study using the selective PKC inhibitors, GF10903X (0.5 - 1 μM) and staurosporine (400 nM).</p> <p>Methods</p> <p>Alterations in cytosolic Ca²⁺, Ca²⁺influx, inositol triphosphate (IP₃), and leukotriene B₄production were measured using spectrofluorimetric, radiometric and competitive binding radioreceptor and immunoassay procedures, respectively.</p> <p>Results</p> <p>Activation of the cells with PAF was accompanied by an abrupt increase in cytosolic Ca²⁺followed by a gradual decline towards basal levels. Pretreatment of neutrophils with the PKC inhibitors significantly increased IP₃production with associated enhanced Ca²⁺release from storage vesicles, prolongation of the peak cytosolic Ca²⁺transients, delayed clearance and exaggerated reuptake of the cation, and markedly increased synthesis of LTB₄. The alterations in Ca²⁺fluxes observed with the PKC inhibitors were significantly attenuated by U73122, a PLC inhibitor, as well as by cyclic AMP-mediated upregulation of the Ca²⁺-resequestering endomembrane ATPase.</p> <p>Taken together, these observations are compatible with a mechanism whereby PKC negatively modulates the activity of PLC, with consequent suppression of IP₃production and down-regulation of Ca²⁺mediated pro-inflammatory responses of PAF-activated neutrophils.</p> <p>Conclusion</p> <p>Although generally considered to initiate and/or amplify intracellular signalling cascades which activate and sustain the pro-inflammatory activities of neutrophils and other cell types, the findings of the current study have identified a potentially important physiological, anti-inflammatory function for PKC, at least in neutrophils.</p

The Potential Effect of Using the Cockcroft-Gault Method on Tenofovir-Associated Renal Impairment Reports and on Clinical Decisions Regarding Tenofovir Use in Individual Patients: Implications for the Future

Introduction: In Namibia, the Cockcroft-Gault (C-G) method is recommended for monitoring renal function in HIV patients receiving tenofovir disoproxil fumarate (TDF)-containing combination antiretroviral therapy (cART). However, there are concerns with the potential over-reporting of TDF-associated renal impairment. Methods: Retrospective study comparing the renal function of patients receiving 2nd line cART with either C-G or Chronic Kidney Disease-Epidemiology (CKD-EPI) methods. Results: 71 patients were included. The majority (62%) received TDF-containing 1st line ART. All received 2nd-line cART containing TDF/ lamivudine (3TC)/ zidovudine (AZT) and LPV/r. Before switching to 2nd-line cART, 40.8% and 8.5% had abnormal eGFR according to C-G and CKD-EPI methods respectively. During 2nd-line cART, 47.9% and 7% of patients had abnormal eGFR by C-G and CKD-EPI methods, respectively, and 4.1% and 2.8% respectively experienced a decline in eGFR. There was a significant lack of agreement between the two methods. Conclusion: The C-G method has the potential to report more cases of TDF-associated renal impairment. Consequently, national guidelines in Namibia and other pertinent countries should be reviewed if this is the recommended method for monitoring renal function