Development and verification of a full physiologically-based pharmacokinetic model for sublingual buprenorphine in healthy adult volunteers that accounts for nonlinear bioavailability.

Sublingual buprenorphine is used for opioid use disorder and neonatal opioid withdrawal syndrome (NOWS). The study aimed to develop a full physiologically-based pharmacokinetic (PBPK) model that can adequately describe dose- and formulation-dependent bioavailability of buprenorphine. Simcyp (v21.0) was used for model construction. Four linear regression models (i.e. untransformed or log-transformed for dose or proportion sublingually absorbed) were explored to describe sublingual absorption of buprenorphine across dose. Published clinical trial data not used in model development were used for verification. The PBPK model's predictive performance was deemed adequate if the geometric means of ratios between predicted and observed (P/O ratios) area under the curve (AUC), peak concentration (Cmax), and time to reach Cmax (Tmax) fell within the 1.25-fold prediction error range. Sublingual buprenorphine absorption was best described by a regression model with logarithmically transformed dose. By integrating this nonlinear absorption profile, the PBPK model adequately predicted buprenorphine pharmacokinetics (PK) following administration of sublingual tablets and solution across a dose range of 2-32 mg, with geometric mean (95% confidence interval) P/O ratios for AUC and Cmax equaling 0.99 (0.86-1.12) and 1.24 (1.09-1.40), respectively, and median (5th to 95th percentile) for Tmax equaling 1.11 (0.69-1.57). A verified PBPK model was developed that adequately predicts dose- and formulation-dependent buprenorphine PK following sublingual administration. Significance Statement The PBPK model developed in this study is the first to adequately predict dose- and formulation-dependent sublingual buprenorphine pharmacokinetics. Accurate prediction was facilitated by the incorporation of a novel nonlinear absorption model. The developed model will serve as the foundation for fetomaternal PBPK modeling to predict maternal and fetal buprenorphine exposures to optimize buprenorphine treatment for neonatal opioid withdrawal syndrome (NOWS).

Predictive Performance of Physiologically Based Pharmacokinetic Modelling of Beta-Lactam Antibiotic Concentrations in Adipose, Bone, and Muscle Tissues.

Physiologically based pharmacokinetic (PBPK) models consist of compartments representing different tissues. As most models are only verified based on plasma concentrations, it is unclear how reliable associated tissue profiles are. This study aimed to assess the accuracy of PBPK-predicted beta-lactam antibiotic concentrations in different tissues and assess the impact of using effect site concentrations for evaluation of target attainment. Adipose, bone, and muscle concentrations of five beta-lactams (piperacillin, cefazolin, cefuroxime, ceftazidime, and meropenem) in healthy adults were collected from literature and compared with PBPK predictions. Model performance was evaluated with average fold errors (AFEs) and absolute AFEs (AAFEs) between predicted and observed concentrations. In total, 26 studies were included, 14 of which reported total tissue concentrations and 12 unbound interstitial fluid (uISF) concentrations. Concurrent plasma concentrations, used as baseline verification of the models, were fairly accurate (AFE: 1.14, AAFE: 1.50). Predicted total tissue concentrations were less accurate (AFE: 0.68, AAFE: 1.89). A slight trend for underprediction was observed but none of the studies had AFE or AAFE values outside threefold. Similarly, predictions of microdialysis-derived uISF concentrations were less accurate than plasma concentration predictions (AFE: 1.52, AAFE: 2.32). uISF concentrations tended to be overpredicted and two studies had AFEs and AAFEs outside threefold. Pharmacodynamic simulations in our case showed only a limited impact of using uISF concentrations instead of unbound plasma concentrations on target attainment rates. The results of this study illustrate the limitations of current PBPK models to predict tissue concentrations and the associated need for more accurate models. SIGNIFICANCE STATEMENT: Clinical inaccessibility of local effect site concentrations precipitates a need for predictive methods for the estimation of tissue concentrations. This is the first study in which the accuracy of PBPK-predicted tissue concentrations of beta-lactam antibiotics in humans were assessed. Predicted tissue concentrations were found to be less accurate than concurrent predicted plasma concentrations. When using PBPK models to predict tissue concentrations, this potential relative loss of accuracy should be acknowledged when clinical tissue concentrations are unavailable to verify predictions.

Use of Developmental Midazolam and 1-Hydroxymidazolam Data with Pediatric Physiologically Based Modeling to Assess Cytochrome P450 3A4 and Uridine Diphosphate Glucuronosyl Transferase 2B4 Ontogeny In Vivo.

Pediatric physiologically based pharmacokinetics modeling in drug development has grown in the past decade but uncertainty remains regarding ontogeny of some drug metabolizing enzymes. In this study, a midazolam and 1-hydroxymidazolam physiologically based pharmacokinetic model (PBPK) model was developed and used to define the ontogeny for hepatic cytochrome P450 (CYP) 3A4 and uridine diphosphate glucuronosyl transferase (UGT) 2B4. Data for model development and pharmacokinetic studies on intravenous midazolam in adults and pediatrics were collated from the literature. The PBPK model was verified in the adult population and then used to compare the performance of two ontogeny profiles for CYP3A4 in terms of parent drug elimination in pediatrics. Four studies also published data on the 1-hydroxymidazolam, and this was used to evaluate the known ontogeny for UGT2B4.For midazolam elimination, the Upreti CYP3A4 ontogeny performed better than Salem; mean error (bias) and mean squared error (precision) were 0.14 and 0.064 compared with 0.69 and 1.21, respectively. For 1-hydroxymidazolam elimination, the Simcyp default ontogeny of UGT2B4 appeared to perform best for studies covering the age range 0.5 to 15.7 years, while for a study in younger ages 0 to 1 years it was the Badee UGT2B4 ontogeny. In preterm neonates, overall expression of UGT appeared to be around 10% of that in adults.Identifying the optimal model of CYP3A4 ontogeny is important for the regulatory use of PBPK. The results for midazolam are conclusive but research about other CYP3A4 metabolized compounds will underpin generalizability of the CYP3A4 ontogeny. UGT2B4 ontogeny is less certain, but this study indicates the most likely scenarios. SIGNIFICANCE STATEMENT: A PBPK model for midazolam and 1-hydroxymidazolam was developed to test various ontogeny scenarios for CYP3A4 and UGT2B4. The CYP3A4 ontogeny of Upreti resulted in more accurate prediction of midazolam CL across nine clinical studies, age range birth to 18 years. 1-Hydroxy midazolam was used as a marker of UGT. The Simcyp default 'no ontogeny' profiles for UGT2B4 performed the best; however, for <1 year of age, there was some evidence of overactivity of this enzyme compared to adults.

Sustainable healthcare education: A systematic review of the evidence and barriers to inclusion.

PURPOSE OF THE ARTICLE: Health professions education is failing to prepare students to practice sustainable healthcare despite the climate crisis an urgent provision of educational opportunities is required. This systematic review aimed to synthesise educational approaches applied to sustainable healthcare education within health professions curricula and critically evaluate their impact. MATERIALS AND METHODS: Databases searched: APA PsycInfo, BEI, CINAHL, Embase, ERIC, Medline, Scopus, Cochrane Library, Web of Science, BASE, DART-Europe, EThOS and ProQuest. Secondary searching techniques were also utilised, with searching conducted October 2021. Eligible studies included healthcare professional students/trainees, exposed to sustainable healthcare education, and evaluated through impact on knowledge, attitudes or skills. Empirical studies of any publication status were included. Non-English language studies were excluded. Eligible studies were quality assessed using JBI (2022) critical appraisal checklists and synthesised narratively. RESULTS: Twenty-three studies were included, comprising 3343 participants and seven health professions. Studies primarily adopted a quasi-experimental design and demonstrated variable quality. Most common educational approaches were workshops and clinical skills sessions, though eight different approaches were observed. Positive impacts were achieved for knowledge, attitudes and skills. CONCLUSIONS: Diverse approaches have been applied to sustainable healthcare education, though no superior approach is evident. Instead, many effective approaches are outlined, to be adopted in alignment with the learning outcomes.

Use of a physiologically based pharmacokinetic-pharmacodynamic model for initial dose prediction and escalation during a paediatric clinical trial.

AIMS: To build and verify a physiologically based pharmacokinetic (PBPK) model for radiprodil in adults and link this to a pharmacodynamic (PD) receptor occupancy (RO) model derived from in vitro data. Adapt this model to the paediatric population and predict starting and escalating doses in infants based on RO. Use the model to guide individualized dosing in a clinical trial in 2- to 14-month-old children with infantile spasms. METHODS: A PBPK model for radiprodil was developed to investigate the systemic exposure of the drug after oral administration in fasted and fed adults; this was then linked to RO via a PD model. The model was then expanded to include developmental physiology and ontogeny to predict escalating doses in infants that would result in a specific RO of 20, 40 and 60% based on average unbound concentration following a twice daily (b.i.d.) dosing regimen. Dose progression in the clinical trial was based on observed concentration-time data against PBPK predictions. RESULTS: For paediatric predictions, the elimination of radiprodil, based on experimental evidence, had no ontogeny. Predicted b.i.d. doses ranged from 0.04 mg/kg for 20% RO, 0.1 mg/kg for 40% RO to 0.21 mg/kg for 60% RO. For all infants recruited in the study, observed concentration-time data following the 0.04 mg/kg and subsequent doses were within the PBPK model predicted 5th and 95th percentiles. CONCLUSION: To our knowledge, this is the first time a PBPK model linked to RO has been used to guide dose selection and escalation in the live phase of a paediatric clinical trial.

Teicoplanin physiologically based pharmacokinetic modeling offers a quantitative assessment of a theoretical influence of serum albumin and renal function on its disposition.

PURPOSE: Variability in teicoplanin pharmacokinetics has been explained by multiple factors such as body weight, renal function, and serum albumin level. To improve mechanistic understanding of the causes of variability, a physiologically based pharmacokinetic (PBPK) model can be used as a systematic platform. In this study, a PBPK model of teicoplanin was developed to quantitatively assess the effects of physiological changes due to disease status using virtual populations. METHODS: Predictive performance of the models was evaluated by comparing simulated and observed concentration-time profiles of teicoplanin. Subsequently, sensitivity analyses were conducted to identify potential factors contributing to individual differences in teicoplanin PK. RESULTS: The developed PBPK model generated concentration-time profiles that were comparable to clinical observations in healthy adults, including Caucasians and Japanese, and after single-dose and multiple-dose administration. The predicted PK parameters (i.e., Cmax, AUC, clearance) were within a two-fold range of the observed data in patients with renal impairments as well as healthy adults. Changes in total and unbound teicoplanin concentrations at 72 h, after various dosing regimens (tested 4-14 mg/kg q12h for three doses as a loading dose and then 4-14 mg/kg daily as a maintenance dose), were sensitive to renal function and serum albumin concentrations. CONCLUSION: The PBPK model of teicoplanin provides mechanistic insight into the factors altering its disposition and allows assessments of the theoretical and quantitative impact of individual changes in physiological parameters on its PK even when an actual assessment with adequate sample sizes of patients is challenging.

Materials for retrograde filling in root canal therapy.

BACKGROUND: Root canal therapy is a sequence of treatments involving root canal cleaning, shaping, decontamination, and obturation. It is conventionally performed through a hole drilled into the crown of the affected tooth, namely orthograde root canal therapy. When it fails, retrograde filling, which seals the root canal from the root apex, is a good alternative. Many materials are used for retrograde filling. Since none meets all the criteria an ideal material should possess, selecting the most efficacious material is of utmost importance. This is an update of a Cochrane Review first published in 2016. OBJECTIVES: To determine the effects of different materials used for retrograde filling in children and adults for whom retrograde filling is necessary in order to save the tooth. SEARCH METHODS: An Information Specialist searched five bibliographic databases up to 21 April 2021 and used additional search methods to identify published, unpublished, and ongoing studies. We also searched four databases in the Chinese language. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) that compared different retrograde filling materials, with the reported success rate that was assessed by clinical or radiological methods for which the follow-up period was at least 12 months. DATA COLLECTION AND ANALYSIS: Records were screened in duplicate by independent screeners. Two review authors extracted data independently and in duplicate. Original trial authors were contacted for any missing information. Two review authors independently assessed the risk of bias of the included studies. We followed Cochrane's statistical guidelines and assessed the certainty of the evidence using GRADE. MAIN RESULTS: We included eight studies, all at high risk of bias, involving 1399 participants with 1471 teeth, published between 1995 and 2019, and six comparisons of retrograde filling materials. - Mineral trioxide aggregate (MTA) versus intermediate restorative material (IRM): there may be little to no effect of MTA compared to IRM on success rate at one year, but the evidence is very uncertain (risk ratio (RR) 1.09, 95% confidence interval (CI) 0.97 to 1.22; I2 = 0%; 2 studies; 222 teeth; very low-certainty evidence). - MTA versus super ethoxybenzoic acid (Super-EBA): there may be little to no effect of MTA compared to Super-EBA on success rate at one year, but the evidence is very uncertain (RR 1.03, 95% CI 0.96 to 1.10; 1 study; 192 teeth; very low-certainty evidence). - Super-EBA versus IRM: the evidence is very uncertain about the effect of Super-EBA compared with IRM on success rate at 1 year, with results indicating Super-EBA may reduce or have no effect on success rate (RR 0.90, 95% CI 0.80 to 1.01; 1 study; 194 teeth; very low-certainty evidence). - Dentine-bonded resin composite versus glass ionomer cement: compared to glass ionomer cement, dentine-bonded resin composite may increase the success rate of the treatment at 1 year, but the evidence is very uncertain (RR 2.39, 95% CI 1.60 to 3.59; 1 study; 122 teeth; very low-certainty evidence). Same result was obtained when considering the root as unit of analysis at one year (RR 1.59, 95% CI 1.20 to 2.09; 1 study; 127 roots; very low-certainty evidence). - Glass ionomer cement versus amalgam: the evidence is very uncertain about the effect of glass ionomer cement compared with amalgam on success rate at one year, with results indicating glass ionomer cement may reduce or have no effect on success rate (RR 0.98, 95% CI 0.86 to 1.12; 1 study; 105 teeth; very low-certainty evidence). - MTA versus root repair material (RRM): there may be little to no effect of MTA compared to RRM on success rate at one year, but the evidence is very uncertain (RR 1.00, 95% CI 0.94 to 1.07; I2 = 0%; 2 studies; 278 teeth; very low-certainty evidence). Adverse events were not assessed by any of the included studies. AUTHORS' CONCLUSIONS: Based on the present limited evidence, there is insufficient evidence to draw any conclusion as to the benefits of any one material over another for retrograde filling in root canal therapy. We conclude that more high-quality RCTs are required.

Impact of Cognitive Measures and Sleep on Acute Squat Strength Performance and Perceptual Responses Among Well-Trained Men and Women.

ABSTRACT: Haischer, MH, Cooke, DM, Carzoli, JP, Johnson, TK, Shipherd, AM, Zoeller, RF, Whitehurst, M, and Zourdos, MC. Impact of cognitive measures and sleep on acute squat strength performance and perceptual responses among well-trained men and women. J Strength Cond Res 35(2S): S16-S22, 2021-This study assessed the efficacy of currently used assessments for sleep, anxiety, and stress in predicting 1-repetition maximum (1RM) back squat performance. Fifty-three men (age, 23 ± 3 years; body mass, 86.67 ± 13.93 kg; training age, 6.0 ± 2.5 years; 1RM = 163.5 ± 39.5 kg) and 15 women (age, 21 ± 1.5 years; body mass, 63.34 ± 9.6 kg; training age, 4 ± 1.5 years; 1RM = 81.5 ± 12.5 kg) participated. Subjects completed the Daily Analysis of Life Demands for Athletes (DALDA), the revised Competitive State Anxiety Inventory-2 (CSAI-2R), and Oviedo Sleep Questionnaire (OSQ) to evaluate stress, anxiety, and sleep, respectively. Subjects then completed the perceived self-efficacy (PSE) scale, to predict what loads they were 100, 75, and 50% confident that they could lift for a 1RM; then completed 1RM testing with rating of perceived exertion (RPE) and average concentric velocity (ACV) obtained on each attempt. The performance-dependent variable was calculated by subtracting the PSE responses from the actual 1RM (1RM-PSE difference). Bootstrapping with 1,000 replicate samples was used with linear regression to increased robustness of the statistical analyses, and 95% confidence intervals (CIs) were calculated. Hours of sleep was an inverse predictor of ACV (p = 0.014; 95% CI = 0.046 to-0.011) and a positive predictor of RPE (p = 0.005; 95% CI = 0.068-0.342). Furthermore, the hypersomnia subscale of the OSQ was a negative predictor of 1RM-PSE difference at 50% confidence (p = 0.028; 95% CI = -3.507 to -0.528), and CSAI-2R total score was a negative predictor of RPE at 1RM (p = 0.043; 95% CI = -0.041 to -0.003); however, the DALDA did not exhibit any significant relationships. These data highlight the importance of monitoring anxiety and sleep when assessing readiness for maximal strength performance.

Effects of Eupalinilide E and UM171, alone and in combination on cytokine stimulated ex-vivo expansion of human cord blood hematopoietic stem cells.

Eupalinilide E was assessed for ex-vivo expansion activity on hematopoietic stem cells (HSCs) from human cord blood (CB) CD34+ cells in serum-free, SCF, TPO and FL stimulated 7 day cultures. Eupalinilide E ex-vivo enhanced phenotyped (p) HSCs and glycolysis of CD34+ cells isolated 7 days after culture as measured by extracellular acidification rate, but did not alone show enhanced NSG engrafting capability of HSCs as determined by chimerism and numbers of SCID Repopulating cells, a quantitative measure of functional human HSCs. This is another example of pHSCs not necessarily recapitulating functional activity of these cells. Lack of effect on engrafting HSCs may be due to a number of possibilities, including down regulation of CXCR4 or of the homing capacity of these treated cells. However, Eupalinilide did act in an additive to synergistic fashion with UM171 to enhance ex vivo expansion of both pHSCs, and functionally engrafting HSCs. While reasons for the disconnect between pHSC and function of HSCs with Eupalinilide E alone cultured CB CD34+ cells is yet to be determined, the data suggest possible future use of Eupalinilide and UM171 together to enhance ex vivo production of CB HSCs for clinical hematopoietic cell transplantation.

Adjunctive systemic antimicrobials for the non-surgical treatment of periodontitis.

BACKGROUND: Systemic antimicrobials can be used as an adjunct to mechanical debridement (scaling and root planing (SRP)) as a non-surgical treatment approach to manage periodontitis. A range of antibiotics with different dosage and combinations are documented in the literature. The review follows the previous classification of periodontitis as all included studies used this classification. OBJECTIVES: To assess the effects of systemic antimicrobials as an adjunct to SRP for the non-surgical treatment of patients with periodontitis. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following databases to 9 March 2020: Cochrane Oral Health's Trials Register, CENTRAL, MEDLINE, and Embase. The US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials. SELECTION CRITERIA: We included randomized controlled trials (RCTs) which involved individuals with clinically diagnosed untreated periodontitis. Trials compared SRP with systemic antibiotics versus SRP alone/placebo, or with other systemic antibiotics. DATA COLLECTION AND ANALYSIS: We selected trials, extracted data, and assessed risk of bias in duplicate. We estimated mean differences (MDs) for continuous data, with 95% confidence intervals (CIs). We assessed the certainty of the evidence using GRADE. MAIN RESULTS: We included 45 trials conducted worldwide involving 2664 adult participants. 14 studies were at low, 8 at high, and the remaining 23 at unclear overall risk of bias. Seven trials did not contribute data to the analysis. We assessed the certainty of the evidence for the 10 comparisons which reported long-term follow-up (≥ 1 year). None of the studies reported data on antimicrobial resistance and patient-reported quality of life changes. Amoxicillin + metronidazole + SRP versus SRP in chronic/aggressive periodontitis: the evidence for percentage of closed pockets (MD -16.20%, 95% CI -25.87 to -6.53; 1 study, 44 participants); clinical attachment level (CAL) (MD -0.47 mm, 95% CI -0.90 to -0.05; 2 studies, 389 participants); probing pocket depth (PD) (MD -0.30 mm, 95% CI -0.42 to -0.18; 2 studies, 389 participants); and percentage of bleeding on probing (BOP) (MD -8.06%, 95% CI -14.26 to -1.85; 2 studies, 389 participants) was of very low certainty. Only the results for closed pockets and BOP showed a minimally important clinical difference (MICD) favouring amoxicillin + metronidazole + SRP. Metronidazole + SRP versus SRP in chronic/aggressive periodontitis: the evidence for percentage of closed pockets (MD -12.20%, 95% CI -29.23 to 4.83; 1 study, 22 participants); CAL (MD -1.12 mm, 95% CI -2.24 to 0; 3 studies, 71 participants); PD (MD -1.11 mm, 95% CI -2.84 to 0.61; 2 studies, 47 participants); and percentage of BOP (MD -6.90%, 95% CI -22.10 to 8.30; 1 study, 22 participants) was of very low certainty. Only the results for CAL and PD showed an MICD favouring the MTZ + SRP group. Azithromycin + SRP versus SRP for chronic/aggressive periodontitis: we found no evidence of a difference in percentage of closed pockets (MD 2.50%, 95% CI -10.19 to 15.19; 1 study, 40 participants); CAL (MD -0.59 mm, 95% CI -1.27 to 0.08; 2 studies, 110 participants); PD (MD -0.77 mm, 95% CI -2.33 to 0.79; 2 studies, 110 participants); and percentage of BOP (MD -1.28%, 95% CI -4.32 to 1.76; 2 studies, 110 participants) (very low-certainty evidence for all outcomes). Amoxicillin + clavulanate + SRP versus SRP for chronic periodontitis: the evidence from 1 study, 21 participants for CAL (MD 0.10 mm, 95% CI -0.51 to 0.71); PD (MD 0.10 mm, 95% CI -0.17 to 0.37); and BOP (MD 0%, 95% CI -0.09 to 0.09) was of very low certainty and did not show a difference between the groups. Doxycycline + SRP versus SRP in aggressive periodontitis: the evidence from 1 study, 22 participants for CAL (MD -0.80 mm, 95% CI -1.49 to -0.11); and PD (MD -1.00 mm, 95% CI -1.78 to -0.22) was of very low certainty, with the doxycycline + SRP group showing an MICD in PD only. Tetracycline + SRP versus SRP for aggressive periodontitis: we found very low-certainty evidence of a difference in long-term improvement in CAL for the tetracycline group (MD -2.30 mm, 95% CI -2.50 to -2.10; 1 study, 26 participants). Clindamycin + SRP versus SRP in aggressive periodontitis: we found very low-certainty evidence from 1 study, 21 participants of a difference in long-term improvement in CAL (MD -1.70 mm, 95% CI -2.40 to -1.00); and PD (MD -1.80 mm, 95% CI -2.47 to -1.13) favouring clindamycin + SRP. Doxycycline + SRP versus metronidazole + SRP for aggressive periodontitis: there was very low-certainty evidence from 1 study, 27 participants of a difference in long-term CAL (MD 1.10 mm, 95% CI 0.36 to 1.84); and PD (MD 1.00 mm, 95% CI 0.30 to 1.70) favouring metronidazole + SRP. Clindamycin + SRP versus metronidazole + SRP for aggressive periodontitis: the evidence from 1 study, 26 participants for CAL (MD 0.20 mm, 95% CI -0.55 to 0.95); and PD (MD 0.20 mm, 95% CI -0.38 to 0.78) was of very low certainty and did not show a difference between the groups. Clindamycin + SRP versus doxycycline + SRP for aggressive periodontitis: the evidence from 1 study, 23 participants for CAL (MD -0.90 mm, 95% CI -1.62 to -0.18); and PD (MD -0.80 mm, 95% CI -1.58 to -0.02) was of very low certainty and did not show a difference between the groups. Most trials testing amoxicillin, metronidazole, and azithromycin reported adverse events such as nausea, vomiting, diarrhoea, mild gastrointestinal disturbances, and metallic taste. No serious adverse events were reported. AUTHORS' CONCLUSIONS: There is very low-certainty evidence (for long-term follow-up) to inform clinicians and patients if adjunctive systemic antimicrobials are of any help for the non-surgical treatment of periodontitis. There is insufficient evidence to decide whether some antibiotics are better than others when used alongside SRP. None of the trials reported serious adverse events but patients should be made aware of the common adverse events related to these drugs. Well-planned RCTs need to be conducted clearly defining the minimally important clinical difference for the outcomes closed pockets, CAL, PD, and BOP.

Development of a physiologically based pharmacokinetic model for mefloquine and its application alongside a clinical effectiveness model to select an optimal dose for prevention of malaria in young Caucasian children.

AIMS: To predict the optimal chemoprophylactic dose of mefloquine in infants of 5-10 kg using physiologically based pharmacokinetic (PBPK) and clinical effectiveness models. METHODS: The PBPK model was developed in Simcyp version 14.1 and verified against clinical pharmacokinetic data in adults; the final model, accounting for developmental physiology and enzyme ontogeny was then applied in the paediatric population. The clinical effectiveness model utilized real-world chemoprophylaxis data with stratification of output by age and including infant data from the UK population. RESULTS: PBPK simulations in infant populations depend on the assumed fraction of mefloquine metabolized by CYP3A4 (0.47, 0.95) and on the associated CYP3A4 ontogeny (Salem, Upreti). However, all scenarios suggest that a dose of 62.5 mg weekly achieves or exceeds the exposure in adults following a 250 mg weekly dose and results in a minimum plasma concentration of 620 ng ml-1 , which is considered necessary to achieve 95% prophylactic efficacy. The clinical effectiveness model predicts a 96% protective efficacy from mefloquine chemoprophylaxis at 62.5 mg weekly. CONCLUSIONS: The PBPK and clinical effectiveness models are mutually supportive and suggest a prophylactic dose of 62.5 mg weekly in the Caucasian 5-10 kg infant population travelling to endemic countries. This dual approach offers a novel route to dose selection in a vulnerable population, where clinical trials would be difficult to conduct.

Directing Stem Cell Fate: The Synthetic Natural Product Connection.

Stem cells possess remarkable potential for the treatment of a broad array of diseases including many that lack therapeutic options. However, the use of cell-based products derived from stem cells as therapeutics has limitations including rejection, sufficient availability, and lack of appropriate engraftment. Chemical control of stem cells provides potential solutions for overcoming many of the current limitations in cell-based therapeutics. The development of exogenous molecules to control stem cell self-renewal or differentiation has arrived at natural product-based agents as an important class of modulators. The ex vivo production of cryopreserved cellular products for use in tissue repair is a relatively new area of medicine in which the conventional hurdles to implementing chemicals to effect human health are changed. Translational challenges centered on chemistry, such as pharmacokinetics, are reduced. Importantly, in many cases the desired human tissues can be evaluated against new chemicals, and approaches to cellular regulation can be validated in the clinically applicable system. As a result linking new and existing laboratory syntheses of natural products with findings of the compounds' unique abilities to regulate stem cell fate provides opportunities for developing improved methods for tissue manufacture, accessing probe compounds, and generating new leads that yield manufactured cells with improved properties. This review provides a summary of natural products that have shown promise in controlling stem cell fate and which have also been fully synthesized thereby providing chemistry platforms for further development.

WITHDRAWN: Ozone therapy for the treatment of dental caries.

BACKGROUND: Dental caries is a bacterially mediated disease characterised by demineralisation of the tooth surface, which may lead to cavitation, discomfort, pain and eventual tooth loss. Ozone is toxic to certain bacteria in vitro and it has been suggested that delivering ozone into a carious lesion might reduce the number of cariogenic bacteria. This possibly could arrest the progress of the lesion and may, in the presence of fluoride, perhaps allow remineralisation to occur. This may in turn delay or prevent the need for traditional dental conservation by 'drilling and filling'. OBJECTIVES: To assess whether ozone is effective in arresting or reversing the progression of dental caries. SEARCH METHODS: We searched the Cochrane Oral Health Group's Trials Register (to 7 November 2003); Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2003, Issue 3); MEDLINE and PREMEDLINE (OVID) (1966 to November 2003); EMBASE (OVID) (1980 to November 2003); CINAHL (OVID) (1982 to November 2003); AMED (OVID) (1985 to November 2003). Quintessence was handsearched through 2002 and KaVo were contacted as manufacturers of the HealOzone apparatus for any additional published or unpublished trials. SELECTION CRITERIA: Inclusion was assessed independently by at least two reviewers. Trials were only included if they met the following criteria: randomisation in a controlled trial; single surface in vivo carious lesion accessible to ozone application; clear allocation concealment; ozone application to the lesions in the intervention group; no such application of ozone in the control group; outcomes measured after at least 6 months. DATA COLLECTION AND ANALYSIS: Reviewers independently extracted information in duplicate. A paucity of comparable data did not allow meta-analytic pooling of the included studies. MAIN RESULTS: Three trials were included, with a combined total of 432 randomised lesions (137 participants). Forty-two conference papers, abstracts and posters were excluded (from an unknown number of studies). The risk of bias in all studies appeared high. The analyses of all three studies were conducted at the level of the lesion, which is not independent of the person, for this reason pooling of data was not appropriate or attempted. Individual studies showed inconsistent effects of ozone on caries, across different measures of caries progression or regression. Few secondary outcomes were reported, but one trial reported an absence of adverse events. AUTHORS' CONCLUSIONS: Given the high risk of bias in the available studies and lack of consistency between different outcome measures, there is no reliable evidence that application of ozone gas to the surface of decayed teeth stops or reverses the decay process. There is a fundamental need for more evidence of appropriate rigour and quality before the use of ozone can be accepted into mainstream primary dental care or can be considered a viable alternative to current methods for the management and treatment of dental caries.

Home use of interdental cleaning devices, in addition to toothbrushing, for preventing and controlling periodontal diseases and dental caries.

BACKGROUND: Dental caries (tooth decay) and periodontal diseases (gingivitis and periodontitis) affect the majority of people worldwide, and treatment costs place a significant burden on health services. Decay and gum disease can cause pain, eating and speaking difficulties, low self-esteem, and even tooth loss and the need for surgery. As dental plaque is the primary cause, self-administered daily mechanical disruption and removal of plaque is important for oral health. Toothbrushing can remove supragingival plaque on the facial and lingual/palatal surfaces, but special devices (such as floss, brushes, sticks, and irrigators) are often recommended to reach into the interdental area. OBJECTIVES: To evaluate the effectiveness of interdental cleaning devices used at home, in addition to toothbrushing, compared with toothbrushing alone, for preventing and controlling periodontal diseases, caries, and plaque. A secondary objective was to compare different interdental cleaning devices with each other. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched: Cochrane Oral Health's Trials Register (to 16 January 2019), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2018, Issue 12), MEDLINE Ovid (1946 to 16 January 2019), Embase Ovid (1980 to 16 January 2019) and CINAHL EBSCO (1937 to 16 January 2019). The US National Institutes of Health Trials Registry (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials. No restrictions were placed on the language or date of publication. SELECTION CRITERIA: Randomised controlled trials (RCTs) that compared toothbrushing and a home-use interdental cleaning device versus toothbrushing alone or with another device (minimum duration four weeks). DATA COLLECTION AND ANALYSIS: At least two review authors independently screened searches, selected studies, extracted data, assessed studies' risk of bias, and assessed evidence certainty as high, moderate, low or very low, according to GRADE. We extracted indices measured on interproximal surfaces, where possible. We conducted random-effects meta-analyses, using mean differences (MDs) or standardised mean differences (SMDs). MAIN RESULTS: We included 35 RCTs (3929 randomised adult participants). Studies were at high risk of performance bias as blinding of participants was not possible. Only two studies were otherwise at low risk of bias. Many participants had a low level of baseline gingival inflammation.Studies evaluated the following devices plus toothbrushing versus toothbrushing: floss (15 trials), interdental brushes (2 trials), wooden cleaning sticks (2 trials), rubber/elastomeric cleaning sticks (2 trials), oral irrigators (5 trials). Four devices were compared with floss: interdental brushes (9 trials), wooden cleaning sticks (3 trials), rubber/elastomeric cleaning sticks (9 trials) and oral irrigators (2 trials). Another comparison was rubber/elastomeric cleaning sticks versus interdental brushes (3 trials).No trials assessed interproximal caries, and most did not assess periodontitis. Gingivitis was measured by indices (most commonly, Löe-Silness, 0 to 3 scale) and by proportion of bleeding sites. Plaque was measured by indices, most often Quigley-Hein (0 to 5). PRIMARY OBJECTIVE: comparisons against toothbrushing aloneLow-certainty evidence suggested that flossing, in addition to toothbrushing, may reduce gingivitis (measured by gingival index (GI)) at one month (SMD -0.58, 95% confidence interval (CI) -1.12 to -0.04; 8 trials, 585 participants), three months or six months. The results for proportion of bleeding sites and plaque were inconsistent (very low-certainty evidence).Very low-certainty evidence suggested that using an interdental brush, plus toothbrushing, may reduce gingivitis (measured by GI) at one month (MD -0.53, 95% CI -0.83 to -0.23; 1 trial, 62 participants), though there was no clear difference in bleeding sites (MD -0.05, 95% CI -0.13 to 0.03; 1 trial, 31 participants). Low-certainty evidence suggested interdental brushes may reduce plaque more than toothbrushing alone (SMD -1.07, 95% CI -1.51 to -0.63; 2 trials, 93 participants).Very low-certainty evidence suggested that using wooden cleaning sticks, plus toothbrushing, may reduce bleeding sites at three months (MD -0.25, 95% CI -0.37 to -0.13; 1 trial, 24 participants), but not plaque (MD -0.03, 95% CI -0.13 to 0.07).Very low-certainty evidence suggested that using rubber/elastomeric interdental cleaning sticks, plus toothbrushing, may reduce plaque at one month (MD -0.22, 95% CI -0.41 to -0.03), but this was not found for gingivitis (GI MD -0.01, 95% CI -0.19 to 0.21; 1 trial, 12 participants; bleeding MD 0.07, 95% CI -0.15 to 0.01; 1 trial, 30 participants).Very-low certainty evidence suggested oral irrigators may reduce gingivitis measured by GI at one month (SMD -0.48, 95% CI -0.89 to -0.06; 4 trials, 380 participants), but not at three or six months. Low-certainty evidence suggested that oral irrigators did not reduce bleeding sites at one month (MD -0.00, 95% CI -0.07 to 0.06; 2 trials, 126 participants) or three months, or plaque at one month (SMD -0.16, 95% CI -0.41 to 0.10; 3 trials, 235 participants), three months or six months, more than toothbrushing alone. SECONDARY OBJECTIVE: comparisons between devicesLow-certainty evidence suggested interdental brushes may reduce gingivitis more than floss at one and three months, but did not show a difference for periodontitis measured by probing pocket depth. Evidence for plaque was inconsistent.Low- to very low-certainty evidence suggested oral irrigation may reduce gingivitis at one month compared to flossing, but very low-certainty evidence did not suggest a difference between devices for plaque.Very low-certainty evidence for interdental brushes or flossing versus interdental cleaning sticks did not demonstrate superiority of either intervention.Adverse eventsStudies that measured adverse events found no severe events caused by devices, and no evidence of differences between study groups in minor effects such as gingival irritation. AUTHORS' CONCLUSIONS: Using floss or interdental brushes in addition to toothbrushing may reduce gingivitis or plaque, or both, more than toothbrushing alone. Interdental brushes may be more effective than floss. Available evidence for tooth cleaning sticks and oral irrigators is limited and inconsistent. Outcomes were mostly measured in the short term and participants in most studies had a low level of baseline gingival inflammation. Overall, the evidence was low to very low-certainty, and the effect sizes observed may not be clinically important. Future trials should report participant periodontal status according to the new periodontal diseases classification, and last long enough to measure interproximal caries and periodontitis.

WITHDRAWN: Interdental brushing for the prevention and control of periodontal diseases and dental caries in adults.

BACKGROUND: Effective oral hygiene is a crucial factor in maintaining good oral health, which is associated with overall health and health-related quality of life. Dental floss has been used for many years in conjunction with toothbrushing for removing dental plaque in between teeth, however, interdental brushes have been developed which many people find easier to use than floss, providing there is sufficient space between the teeth. OBJECTIVES: To evaluate the effects of interdental brushing in addition to toothbrushing, as compared with toothbrushing alone or toothbrushing and flossing for the prevention and control of periodontal diseases, dental plaque and dental caries. SEARCH METHODS: We searched the following electronic databases: the Cochrane Oral Health Group's Trials Register (to 7 March 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 2), MEDLINE via OVID (1946 to 7 March 2013), EMBASE via OVID (1980 to 7 March 2013), CINAHL via EBSCO (1980 to 7 March 2013), LILACS via BIREME (1982 to 7 March 2013), ZETOC Conference Proceedings (1980 to 7 March 2013) and Web of Science Conference Proceedings (1990 to 7 March 2013). We searched the US National Institutes of Health Trials Register (http://clinicaltrials.gov) and the metaRegister of Controlled Trials (http://www.controlled-trials.com/mrct/) for ongoing trials to 7 March 2013. No restrictions were placed on the language or date of publication when searching the electronic databases. SELECTION CRITERIA: We included randomised controlled trials (including split-mouth design, cross-over and cluster-randomised trials) of dentate adult patients. The interventions were a combination of toothbrushing and any interdental brushing procedure compared with toothbrushing only or toothbrushing and flossing. DATA COLLECTION AND ANALYSIS: At least two review authors assessed each of the included studies to confirm eligibility, assessed risk of bias and extracted data using a piloted data extraction form. We calculated standardised mean difference (SMD) and 95% confidence interval (CI) for continuous outcomes where different scales were used to assess an outcome. We attempted to extract data on adverse effects of interventions. Where data were missing or unclear we attempted to contact study authors to obtain further information. MAIN RESULTS: There were seven studies (total 354 participants analysed) included in this review. We assessed one study as being low, three studies as being high and three studies as being at unclear risk of bias. Studies only reported the clinical outcome gingivitis and plaque data, with no studies providing data on many of the outcomes: periodontitis, caries, halitosis and quality of life. Three studies reported that no adverse events were observed or reported during the study. Two other studies provided some data on adverse events but we were unable to pool the data due to lack of detail. Two studies did not report whether adverse events occurred.Interdental brushing in addition to toothbrushing, as compared with toothbrushing aloneOnly one high risk of bias study (62 participants in analysis) looked at this comparison and there was very low-quality evidence for a reduction in gingivitis (0 to 4 scale, mean in control): mean difference (MD) 0.53 (95% CI 0.23 to 0.83) and plaque (0 to 5 scale): MD 0.95 (95% CI 0.56 to 1.34) at one month, favouring of use of interdental brushes. This represents a 34% reduction in gingivitis and a 32% reduction in plaque.Interdental brushing in addition to toothbrushing, as compared with toothbrushing and flossingSeven studies provided data showing a reduction in gingivitis in favour of interdental brushing at one month: SMD -0.53 (95% CI -0.81 to -0.24, seven studies, 326 participants, low-quality evidence). This translates to a 52% reduction in gingivitis (Eastman Bleeding Index). Although a high effect size in the same direction was observed at three months (SMD -1.98, 95% CI -5.42 to 1.47, two studies, 107 participants, very low quality), the confidence interval was wide and did not exclude the possibility of no difference. There was insufficient evidence to claim a benefit for either interdental brushing or flossing for reducing plaque (SMD at one month 0.10, 95% CI -0.13 to 0.33, seven studies, 326 participants, low-quality evidence) and insufficient evidence at three months (SMD -2.14, 95% CI -5.25 to 0.97, two studies, 107 participants very low-quality evidence). AUTHORS' CONCLUSIONS: Only one study looked at whether toothbrushing with interdental brushing was better than toothbrushing alone, and there was very low-quality evidence for a reduction in gingivitis and plaque at one month. There is also low-quality evidence from seven studies that interdental brushing reduces gingivitis when compared with flossing, but these results were only found at one month. There was insufficient evidence to determine whether interdental brushing reduced or increased levels of plaque when compared to flossing.

WITHDRAWN: Flossing for the management of periodontal diseases and dental caries in adults.

BACKGROUND: Good oral hygiene is thought to be important for oral health. This review is to determine the effectiveness of flossing in addition to toothbrushing for preventing gum disease and dental caries in adults. OBJECTIVES: To assess the effects of flossing in addition to toothbrushing, as compared with toothbrushing alone, in the management of periodontal diseases and dental caries in adults. SEARCH METHODS: We searched the following electronic databases: the Cochrane Oral Health Group Trials Register (to 17 October 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 4), MEDLINE via OVID (1950 to 17 October 2011), EMBASE via OVID (1980 to 17 October 2011), CINAHL via EBSCO (1980 to 17 October 2011), LILACS via BIREME (1982 to 17 October 2011), ZETOC Conference Proceedings (1980 to 17 October 2011), Web of Science Conference Proceedings (1990 to 17 October 2011), Clinicaltrials.gov (to 17 October 2011) and the metaRegister of Controlled Clinical Trials (to 17 October 2011). We imposed no restrictions regarding language or date of publication. We contacted manufacturers of dental floss to identify trials. SELECTION CRITERIA: We included randomised controlled trials conducted comparing toothbrushing and flossing with only toothbrushing, in adults. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed risk of bias for the included studies and extracted data. We contacted trial authors for further details where these were unclear. The effect measure for each meta-analysis was the standardised mean difference (SMD) with 95% confidence intervals (CI) using random-effects models. We examined potential sources of heterogeneity, along with sensitivity analyses omitting trials at high risk of bias. MAIN RESULTS: Twelve trials were included in this review, with a total of 582 participants in flossing plus toothbrushing (intervention) groups and 501 participants in toothbrushing (control) groups. All included trials reported the outcomes of plaque and gingivitis. Seven of the included trials were assessed as at unclear risk of bias and five were at high risk of bias.Flossing plus toothbrushing showed a statistically significant benefit compared to toothbrushing in reducing gingivitis at the three time points studied, the SMD being -0.36 (95% CI -0.66 to -0.05) at 1 month, SMD -0.41 (95% CI -0.68 to -0.14) at 3 months and SMD -0.72 (95% CI -1.09 to -0.35) at 6 months. The 1-month estimate translates to a 0.13 point reduction on a 0 to 3 point scale for Loe-Silness gingivitis index, and the 3 and 6 month results translate to 0.20 and 0.09 reductions on the same scale.Overall there is weak, very unreliable evidence which suggests that flossing plus toothbrushing may be associated with a small reduction in plaque at 1 or 3 months.None of the included trials reported data for the outcomes of caries, calculus, clinical attachment loss, or quality of life. There was some inconsistent reporting of adverse effects. AUTHORS' CONCLUSIONS: There is some evidence from twelve studies that flossing in addition to toothbrushing reduces gingivitis compared to toothbrushing alone. There is weak, very unreliable evidence from 10 studies that flossing plus toothbrushing may be associated with a small reduction in plaque at 1 and 3 months. No studies reported the effectiveness of flossing plus toothbrushing for preventing dental caries.

Body Mass and Femur Length Are Inversely Related to Repetitions Performed in the Back Squat in Well-Trained Lifters.

Cooke, DM, Haischer, MH, Carzoli, JP, Bazyler, CD, Johnson, TK, Varieur, R, Zoeller, RF, Whitehurst, M, and Zourdos, MC. Body mass and femur length are inversely related to repetitions performed in the back squat in well-trained lifters. J Strength Cond Res 33(3): 890-895, 2019-The purpose of this research note was to examine whether relationships existed between anthropometrics (body mass, body fat percentage [BF%], and femur length) and descriptive characteristics (age and sex) with repetitions performed to failure at 70% of 1 repetition maximum (1RM) in the back squat. Fifty-eight subjects (males = 43, females = 15; age: 23 ± 3 years, training age: 5.5 ± 2.5 years, body mass: 80.65 ± 16.34 kg, BF%: 10.98 ± 3.53%, and femur length: 47.1 ± 2.6 cm) completed a 1RM squat followed by one set to failure at 70% of 1RM. Total repetitions performed at 70% of 1RM were 14 ± 4 (range: 6-26). Bivariate correlations showed significant inverse relationships between body mass (r = -0.352, p = 0.003), BF% (r = -0.278, p = 0.014), and femur length (r = -0.265, p = 0.019), with repetitions performed. No significant relationships existed between age and sex (p > 0.05), with repetitions performed. All these variables entered into a standard multivariate regression. The model R was 0.200, and body mass had the largest influence (p = 0.057) because relative importance analysis demonstrated body mass to contribute to 43.87% of the variance (of the R) in repetitions performed. No other variable was significant or approached significance (p > 0.05). Our results reveal that body mass, BF%, and femur length all are inversely related to repetitions performed at 70% of 1RM in the back squat.

Troubleshooting Hypoxemia After Placement of an Extraglottic Airway.

The case presented here highlights the feasibility of using an extraglottic airway device as a conduit for delivering high levels of lifesaving positive end expiratory pressure (PEEP), as well as other means of combating recalcitrant hypoxia. The case also highlights the merit of an approach to the hypoxic patient with an in-situ extraglottic airway device based not only on deciding if the device is functioning to maintain a patent airway, but also, simultaneously considering the patient's physiology. A 71 year old male suffered an out-of-hospital cardiac arrest. Part of his resuscitation included placement of a dual-balloon extraglottic airway device by EMS. He was hypoxic, but the device seemed to be providing for a patent airway without an air leak. There was also a favorable end-tidal carbon dioxide waveform. The flight team chose to the leave the device in place. PEEP was up-titrated to 17 cmH20 without issue. Sigh breaths, as well as breath holds, were also able to be delivered. The patient's hypoxia improved over the course of the patient's transport, and he ultimately did well.

Can Population Modelling Principles be Used to Identify Key PBPK Parameters for Paediatric Clearance Predictions? An Innovative Application of Optimal Design Theory.

PURPOSE: Physiologically-based pharmacokinetic (PBPK) models are essential in drug development, but require parameters that are not always obtainable. We developed a methodology to investigate the feasibility and requirements for precise and accurate estimation of PBPK parameters using population modelling of clinical data and illustrate this for two key PBPK parameters for hepatic metabolic clearance, namely whole liver unbound intrinsic clearance (CLint,u,WL) and hepatic blood flow (Qh) in children. METHODS: First, structural identifiability was enabled through re-parametrization and the definition of essential trial design components. Subsequently, requirements for the trial components to yield precise estimation of the PBPK parameters and their inter-individual variability were established using a novel application of population optimal design theory. Finally, the performance of the proposed trial design was assessed using stochastic simulation and estimation. RESULTS: Precise estimation of CLint,u,WL and Qh and their inter-individual variability was found to require a trial with two drugs, of which one has an extraction ratio (ER) ≤ 0.27 and the other has an ER ≥ 0.93. The proposed clinical trial design was found to lead to precise and accurate parameter estimates and was robust to parameter uncertainty. CONCLUSION: The proposed framework can be applied to other PBPK parameters and facilitate the development of PBPK models.