Interindividual variability of aminoglycoside pharmacokinetics in preterm neonates at birth.
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Amikacin↗
Biomedical subjects
Brian J Anderson
Publications and source records attributed to Brian J Anderson.
Vancomycin pharmacokinetics in preterm neonates and the prediction of adult clearance.
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: *Effects of size, renal function, age (postnatal age, gestational age and postmenstrual age) as predictors of vancomycin clearance in premature neonates are established, but the relative contribution of each component remains poorly quantified, largely because these variables are closely correlated. *We have quantified the covariates contributing to vancomycin clearance population parameter variability in order to establish the major covariates required for dosing predictions. Size, standardized using allometric models, was the primary covariate used in our analysis. WHAT THIS STUDY ADDS: *Size explained 49.8%, postmenstrual age 18.2% and renal function 14.1% of clearance variability. *Descriptors of the relationship between age and clearance in premature neonates vary. *The use of a variable slope sigmoidal model to describe the relationship between clearance and postmenstrual age predicted an adult clearance of 3.79 l h(-1) 70 kg(-1) (95% confidence interval 2.76, 4.98) from premature neonatal data. AIM: To identify and quantify factors describing the variability of vancomycin clearance in premature neonates. METHODS: Population pharmacokinetics were estimated (NONMEM) in 214 neonates [postmenstrual age (PMA) 30.4 weeks, range 24-34 weeks; postnatal age 11.9 days, range 1-27 days; weight 1.30 kg, range 0.42-2.6 kg] using therapeutic drug monitoring data. Covariate analysis included weight, PMA, serum creatinine, use of inotropes or ibuprofen, positive blood culture and respiratory support. A one-compartment linear disposition model with zero order input and first-order elimination was used to describe the data (604 observations). RESULTS: The population estimate for volume of distribution (V) was 39 l 70 kg(-1) (coefficient of variation 19.4%). Clearance (CL) increased from 0.897 l h(-1) 70 kg(-1) at 24 weeks PMA to 2.02 l h(-1) 70 kg(-1) by 34 weeks PMA. The between-subject variability for CL was 18.6% and the between-occasion variability was 12.2%. The use of ibuprofen reduced clearance, but this effect was attributable to reduced renal function. Overall, 82% of the variability of CL was predictable. Size explained 49.8%, PMA 18.2% and renal function 14.1%. The use of a variable slope sigmoidal model to describe the relationship between clearance and PMA predicted an adult clearance of 3.79 l h(-1) 70 kg(-1) (95% confidence interval 2.76, 4.98). CONCLUSIONS: Size, renal function and PMA are the major contributors to clearance variability in premature neonates. The small (18%) unexplained variability in clearance suggests target concentration intervention is unnecessary if size, age and renal function are used to predict the dose. Extrapolation to an adult clearance from neonatal data is possible using allometric size models and a function describing clearance maturation.
Adult↗
Population clinical pharmacology of children: general principles.
INTRODUCTION: Population modelling using mixed-effects models provides a means to study variability in drug responses among individuals representative of those for whom the drug will be used clinically. DISCUSSION: The advantages of these models in paediatric studies are that they can be used to analyse sparse data, sampling times are not crucial and can be fitted around clinical procedures and individuals with missing data may still be included in the analysis. The introduction of explanatory covariates explains the predictable part of the between-individual variability. Simulations using parameter estimates and their variability can be used to investigate large numbers of children--many more than is possible in studies dealing with real children--for a fraction of the cost, which is an advantage when developing clinical trials. Paediatric population modelling has expanded greatly in the past decade and is now a routine procedure during the development and investigation of drugs. Children have benefitted and will continue to benefit from this approach.
Child↗
Population clinical pharmacology of children: modelling covariate effects.
INTRODUCTION: Population modelling using mixed effects models provides a means to study variability in paediatric drug responses among individuals representative of those in whom the drug will be used clinically. DISCUSSIONS: Explanatory covariates explain the predictable part of the between-individual variability. Growth and development are two major aspects of children not seen in adults. These aspects can be investigated by using size and age as covariates. Problems attributable to co-linearity can be approached by using size as the first covariate. Size standardisation is achieved using allometric scaling, a mechanistic approach that has a strong theoretical and empirical basis. Age is used to describe the maturation of clearance. The quantitative models (linear, exponential, first-order, variable slope sigmoidal) used to describe this maturation process vary depending on the span of the ages under investigation. Measures of response are not always straightforward and can be more difficult to quantify in children. CONCLUSION: Covariate investigation in children is improving the understanding of developmental aspects of drug disposition and effects in the paediatric population, ultimately leading to more effective use of medications.
Body Surface Area↗
Pain control: non-steroidal anti-inflammatory agents.
The non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (paracetamol) are the most common analgesic drugs used in neonates and infants despite limited pharmacodynamic data. Both drugs act through inhibition of cyclooxygenase enzymes. Neonatal acetaminophen clearance is reduced in premature neonates (0.7 L h(-1) x 70 kg(-1)) and increases to 5 L h(-1) x 70 kg(-1) at term (40% adult rates); adult rates are reached within the first year of life; NSAID clearance follows similar trends. Volume of distribution is increased in the neonatal period. Dosing of both drug groups is tempered by concerns about toxicity. Acetaminophen hepatotoxicity is less common in neonates than in older children and adults, possibly due to reduced oxidative enzyme activity (e.g. CYP 2E1). Data concerning NSAID adverse effects in the neonatal period are few. Renal function is reduced 20% after NSAID use for patent ductus arteriosus closure in premature neonates and there is no increased frequency of intraventricular haemorrhage. No significant difference in the change in cerebral blood volume, change in cerebral blood flow, or tissue oxygenation index was found between administration of ibuprofen or placebo in neonates. Future studies should define concentration-response relationships for these drugs that are age and pathology specific.
Absorption↗
A prospective randomised single blinded study comparing harmonic scalpel tonsillectomy with bipolar tonsillectomy.
OBJECTIVE: To compare the differences in pain, analgesic use and bleeding in children after tonsillectomy using either a harmonic scalpel or a bipolar diathermy surgical technique. METHODS: Children 6-15 years presenting for tonsillectomy were randomised to either a harmonic scalpel or bipolar diathermy surgical technique. Post-operative pain scores (VAS, 0-10) were recorded within 30 min of surgery and again at the 4h hospital discharge. A subsequent telephone interview daily for 7 days and then every second day until day 13 was used to monitor pain scores, analgesic use and tonsil bed bleeding. RESULTS: There were 204 children studied. The response rate over the first 7 days was 93% for the children in the harmonic scalpel group and 87% for the bipolar group. Children experienced moderate post-operative pain for the first 6 days, after which pain declined from 4-7 to reach a score of 1-2 by day 11. Children undergoing harmonic scalpel tonsillectomy (n=103) reported higher mean pain scores than those who underwent bipolar diathermy (n=101) for current pain (4.7 versus 4.2, p=0.002), worst pain of the day (6.9 versus 6.2, p<0.001) and pain on swallowing (5.9 versus 5.2, p<0.001) over the first 6 post-operative days. Analgesic use (acetaminophen, ibuprofen) was similar in both groups. Hospital readmission for bleeding in children who underwent harmonic scalpel was similar to those who underwent bipolar diathermy tonsillectomy (9% versus 11%) as was bleeding requiring surgical re-exploration (4% versus 2%). CONCLUSIONS: Tonsillectomy was associated with considerable pain for the first 6 post-operative days. Children undergoing harmonic scalpel tonsillectomy had a slight increase in pain compared to the bipolar diathermy group during this time. Both methods of tonsillectomy are effective and safe.
Adolescent↗
Recent developments in the pharmacological management of pain in children.
PURPOSE OF REVIEW: This review explores progress in developmental pharmacokinetics, pharmacogenomics and formulations of analgesic agents, and discusses potential implications for pain therapy. RECENT FINDINGS: Characterization of the developmental pharmacokinetics of morphine, tramadol, paracetamol and nonsteroidal anti-inflammatory drugs has improved dosing in children. Oral sugar solutions have replaced the brandy/sugar pacifier and are effective for single painful events in neonates. Intravenous paracetamol offers increased dosing accuracy, and avoids absorption and bioavailability variability. New nitric-oxide-releasing versions of paracetamol and nonsteroidal anti-inflammatory drugs offer safer alternatives to their parent drugs with enhanced potency. Ketamine has come under a cloud for its possible effects on the neonatal developing brain, but it is being used increasingly in children to supplement opioids for pain after major surgery. Hopes that morphine analgesia may improve neurological outcome in premature babies have not materialized. Reports concerning chronic pain are generally case series and controlled trials are rare and nearly nonexistent in children. SUMMARY: Unlicensed drug use in the very young will increase as familiarity increases. Pharmacogenomic studies have the potential to tailor drug therapy to the individual and decrease between-patient variability. Unfortunately, the pharmacodynamic knowledge in children of analgesic agents remains neglected and is usually extrapolated from adult data.
Adolescent↗
Limited predictability of amikacin clearance in extreme premature neonates at birth.
AIM: Identify and quantify factors describing variability of amikacin clearance in preterm neonates at birth. METHODS: Population pharmacokinetics of amikacin were estimated in a cohort of 205 extreme preterm neonates [post conception age (PCA) 27.8, SD 1.8, range 24-30 weeks; weight 1.07, SD 0.34, range 0.45-1.98 kg, postnatal age < 72 h]. Covariate analysis included weight, PCA, Apgar score, prophylactic administration of a nonsteroidal anti-inflammatory drug (NSAID) to the neonate, maternal indomethacin and betamethasone administration, and chorioamnionitis. RESULTS: A one-compartment linear disposition model with zero order input (0.3 h i.v. infusion) and first-order elimination was used. The population parameter estimate for volume of distribution (V) was 40.2 l per 70 kg. Clearance (CL) increased from 0.486 l h(-1) per 70 kg at 24 weeks PCA to 0.940 l h(-1) per 70 kg by 30 weeks PCA. The population parameter variability (PPV) for CL and V was 0.336 and 0.451. The use of a NSAID (either aspirin or ibuprofen) in the first day of life reduced amikacin clearance by 22%. Overall 65% of the variability of CL was predictable. Weight explained 48%, PCA 15% and NSAIDs 2%. CONCLUSIONS: Size and post-conception age are the major contributors to clearance variability in extreme premature neonates (<31 weeks PCA). The large (35% of total) unexplained variability in clearance reinforces the need for target concentration intervention to reduce variability in exposure to a safe and effective range.
Age Factors↗
Age and size are the major covariates for prediction of levobupivacaine clearance in children.
BACKGROUND: We aimed to identify and quantify major factors describing the variability of levobupivacaine clearance in children. METHODS: Data from three published studies were used to estimate population pharmacokinetics of levobupivacaine in children who were given epidural regional blockade. Covariate analysis included weight and postnatal age (PNA). Time-concentration profile analysis was undertaken using nonlinear mixed effects models. A one-compartment linear disposition model with first order input and first order elimination was used to describe the data. RESULTS: There were 86 children (weight 9.4, sd 5.5, range 1.9-23 kg; PNA 16.1, sd 22.7, range 0.6-98 months). The population parameter estimate for volume of distribution (V) was 189 l.70 kg(-1). Clearance (CL) was 5.8 l.h(-1).70 kg(-1) at 1-month PNA and increased with a maturation half-time of 2.3 months to reach 80% of the mature value (22.1 l.h(-1).70 kg(-1)) by 6-month PNA. The between subject variability (BSV) for V and CL were 48.5% and 35.2%. Overall, 85.7% of the variability of CL was predictable. Weight alone explained 62.4% and the addition of PNA a further 23.3%. Overall, 69.2% of the variability of V was predictable and attributable to weight; V did not change with age in this cohort. The absorption half-time decreased from 0.36 h at 1-month PNA to 0.14 h (CV 48.1%) at 6-month PNA with a maturation half-time of 0.8 months. CONCLUSIONS: Size and PNA are the major contributors to clearance variability in children. These covariates should be considered when establishing safe epidural infusion regimens. Reduced clearance and slower absorption half-time contribute to delayed T(max) in neonates and young infants.
Age Factors↗
Morphine metabolite pharmacokinetics during venoarterial extra corporeal membrane oxygenation in neonates.
OBJECTIVE: To examine morphine metabolite serum concentrations in neonates undergoing venoarterial extra corporeal membrane oxygenation (ECMO) and to quantify clearance differences between these neonates and those subjected to noncardiac major surgery. PATIENTS AND METHODS: This was an observational study in level III referral centre. Fourteen neonates (< 7 days old) undergoing ECMO were included. Morphine and concomitant medications were given by protocol, adapted to the clinical conditions of the neonates. Pharmacokinetic findings were compared with those from a previous study in infants after noncardiac major surgery. Nonlinear mixed-effect modelling was used. Parameter estimates were standardised to a 70 kg person using allometric modeling RESULTS: Morphine-3-glucuronide (M3G) was the predominant metabolite. Formation clearance to M3G at the start of ECMO on day 1 was lower than those in postoperative children, but matured more rapidly. After 10 days formation clearances of M3G in neonates on ECMO equalled those of postoperative children. Higher ECMO flows were associated with reduced formation clearances. Elimination clearances of M3G, but not morphine-6-glucuronide (M6G), were lower in the ECMO neonates; this was attributable to reduced renal clearance. These elimination clearances were correlated positively with ECMO flow and negatively with dopamine dose. Haemofiltration cleared M3G and M6G, but not morphine. CONCLUSION: Formation clearance to M3G, the predominant metabolite, is reduced during the first 10 days of ECMO. Elimination clearance of M3G and M6G is related to creatinine clearance. ECMO flow had a small effect on metabolite clearance. Higher flows were associated with decreased formation clearances, possibly reflecting illness severity. Dopamine dose reflected decreased renal clearance.
Adult↗
Properties of inhibitors of methane hydrate formation via molecular dynamics simulations.
Within the framework of a proposed two-step mechanism for hydrate inhibition, the energy of binding of four inhibitor molecules (PEO, PVP, PVCap, and VIMA) to a hydrate surface is estimated with molecular dynamic simulations. One key feature of this proposed mechanism is that the binding of an inhibitor molecule to the surface of an ensuing hydrate crystal disrupts growth and therein crystallization. It is found through the molecular dynamic simulations that inhibitor molecules that experimentally exhibit better inhibition strength also have higher free energies of binding, an indirect confirmation of our proposed mechanism. Inhibitors increasing in effectiveness, PEO < PVP < PVCap < VIMA, have increasingly negative (exothermic) binding energies of -0.2 < -20.6 < -37.5 < -45.8 kcal/mol and binding free energies of increasing favorability (+0.4 approximately = +0.5 < -9.4 < -15.1 kcal/mol). Furthermore, the effect of an inhibitor molecule on the local liquid water structure under hydrate-forming conditions was examined and correlated to the experimental effectiveness of the inhibitors. Two molecular characteristics that lead to strongly binding inhibitors were found: (1) a charge distribution on the edge of the inhibitor that mimics the charge separation in the water molecules on the surface of the hydrate and (2) the congruence of the size of the inhibitor with respect to the available space at the hydrate-surface binding site. Equipped with this molecular-level understanding of the process of hydrate inhibition via low-dosage kinetic hydrate inhibitors we can design new, more effective inhibitor molecules.
Journal Article↗
Application of the cell potential method to predict phase equilibria of multicomponent gas hydrate systems.
We present the application of a mathematical method reported earlier by which the van der Waals-Platteeuw statistical mechanical model with the Lennard-Jones and Devonshire approximation can be posed as an integral equation with the unknown function being the intermolecular potential between the guest molecules and the host molecules. This method allows us to solve for the potential directly for hydrates for which the Langmuir constants are computed, either from experimental data or from ab initio data. Given the assumptions made in the van der Waals-Platteeuw model with the spherical-cell approximation, there are an infinite number of solutions; however, the only solution without cusps is a unique central-well solution in which the potential is at a finite minimum at the center to the cage. From this central-well solution, we have found the potential well depths and volumes of negative energy for 16 single-component hydrate systems: ethane (C2H6), cyclopropane (C3H6), methane (CH4), argon (Ar), and chlorodifluoromethane (R-22) in structure I; and ethane (C2H6), cyclopropane (C3H6), propane (C3H8), isobutane (C4H10), methane (CH4), argon (Ar), trichlorofluoromethane (R-11), dichlorodifluoromethane (R-12), bromotrifluoromethane (R-13B1), chloroform (CHCl3), and 1,1,1,2-tetrafluoroethane (R-134a) in structure II. This method and the calculated cell potentials were validated by predicting existing mixed hydrate phase equilibrium data without any fitting parameters and calculating mixture phase diagrams for methane, ethane, isobutane, and cyclopropane mixtures. Several structural transitions that have been determined experimentally as well as some structural transitions that have not been examined experimentally were also predicted. In the methane-cyclopropane hydrate system, a structural transition from structure I to structure II and back to structure I is predicted to occur outside of the known structure II range for the cyclopropane hydrate. Quintuple (L(w)-sI-sII-L(hc)-V) points have been predicted for the ethane-propane-water (277.3 K, 12.28 bar, and x(eth,waterfree) = 0.676) and ethane-isobutane-water (274.7 K, 7.18 bar, and x(eth,waterfree) = 0.81) systems.
Journal Article↗
Morphine pharmacokinetics during venoarterial extracorporeal membrane oxygenation in neonates.
OBJECTIVE: To study morphine pharmacokinetics in neonates undergoing venoarterial ECMO and to quantify differences between these neonates and neonates subjected to noncardiac major surgery. DESIGN AND SETTING: Observational study in a level III referral center. PATIENTS AND METHODS: Pharmacokinetic estimates from 14 neonates undergoing ECMO were compared with findings from a previous study in 0- to 3-year-olds after noncardiac major surgery using a nonlinear mixed effect model. A one-compartment linear disposition model with zero-order input (infusion) and first-order elimination was used to describe all data. RESULTS: Clearance in neonates (age <7 days) at the start of ECMO (2.2 l per hour per 70 kg) was lower than that in postoperative neonates (10.5 l per hour per 70 kg) but increased rapidly (maturation half-life 30 and 70 days, respectively) and equaled that of the postoperative group after 14 days. Clearance was affected by size and age only. Exchange transfusion, when used, contributed only 1.1% (CV 46%) of total clearance. Distribution volume increased with age and was 2.5 times (CV 102%) greater in ECMO children than in postoperative children. The between-subject variability values for volume of distribution and clearance were 49.4% and 38.7%. Weight and age information explained 83% of the overall clearance variability and 60% of overall distribution volume variability. CONCLUSIONS: Morphine clearance is reduced in infants requiring ECMO, possibly reflecting severity of illness. Clearance maturation on ECMO is rapid and normalizes within 2 weeks. Initial morphine dosing may be guided by age and weight, but clearance and distribution volume changes (and their variability) during prolonged ECMO suggests that morphine therapy should be subsequently guided by clinical monitoring.
Chi-Square Distribution↗
Inter- and intramolecular determinants of the specificity of single-stranded DNA binding and cleavage by the F factor relaxase.
The TraI protein of conjugative plasmid F factor binds and cleaves a single-stranded region of the plasmid prior to transfer to a recipient. TraI36, an N-terminal TraI fragment, binds ssDNA with a subnanomolar K(D) and remarkable sequence specificity. The structure of the TraI36 Y16F variant bound to ssDNA reveals specificity determinants, including a ssDNA intramolecular 3 base interaction and two pockets within the protein's binding cleft that accommodate bases in a knob-into-hole fashion. Mutagenesis results underscore the intricate design of the binding site, with the greatest effects resulting from substitutions for residues that both contact ssDNA and stabilize protein structure. The active site architecture suggests that the bound divalent cation, which is essential for catalysis, both positions the DNA by liganding two oxygens of the scissile phosphate and increases the partial positive charge on the phosphorus to enhance nucleophilic attack.
Bacterial Proteins↗
Jet ventilation for laryngotracheal surgery in an ex-premature infant.
A 4-month-old ex-premature infant with severe airway obstruction from subglottic cysts presented for surgical cyst removal. Laryngeal and tracheal surgical procedures in children may present difficulties for the anesthetist because the airway is shared with the surgeon. We report the use of high-frequency jet ventilation (HFJV) to maintain ventilation and provide adequate surgical access. Anesthesia was induced using sevoflurane in oxygen and was maintained with intravenous infusions of propofol 7.5 mg.kg(-1).h(-1) and remifentanil 0.4 microg.kg(-1).min(-1). The suction channel of the ENT laryngoscope was used to introduce an 8-FG ureteric drainage catheter into the larynx and this catheter was used to provide HFJV. Obstruction to expiratory flow was a major concern and was dependent on good positioning of the rigid laryngoscope. Complications such as barotrauma, pneumopericardium, CO2-retention, necrotizing tracheobronchitis, and gastric rupture dictate a fastidious technique.
Airway Obstruction↗
Pediatric intravenous paracetamol (propacetamol) pharmacokinetics: a population analysis.
BACKGROUND: The aim of this study was to describe propacetamol pharmacokinetics in children in order to predict concentrations after a standard dosing regimen of propacetamol 30 mg x kg(-1) (15 mg x kg(-1) paracetamol) 6 h. METHODS: A population pharmacokinetic analysis of paracetamol time-concentration profiles (846 observations) from 144 children [postconception age (PCA) 27 weeks-14 years] was undertaken using nonlinear mixed effects models (NONMEM). These data were taken from seven separate studies involving children given intravenous propacetamol. Time-concentration profiles (503 observations) from a further 86 children (PCA: 37 weeks-14 years) given paracetamol elixir orally were included in the analysis to assess relative bioavailability of intravenous propacetamol. RESULTS: A three-compartment (depot, central and peripheral) linear disposition model fitted data better than a two-compartment (depot and central) model. Population parameter estimates (between subject variability, %) were central volume (V2/F(oral)) 24 (55%) l x 70 kg(-1), peripheral volume of distribution (V3/F(oral)) 30 (32%) l x 70 kg(-1), clearance (CL/F(oral)) 16 (40%) l x h(-1) x 70 kg(-1) and intercompartment clearance (Q/F(oral)) 55 (116%) l x h(-1) x 70 kg(-1). Clearance increased from 27 weeks PCA (1.87 l x h(-1) 70 kg(-1)) to reach 84% of the mature value by 1 year of age (standardized to a 70 kg person using allometric '1/4 power' models). Peripheral volume of distribution decreased from 27 weeks PCA (45.0 l x 70 kg(-1)) to reach 110% of its mature value by 6 months of age. Central volume of distribution and intercompartment clearance did not change with age. Between occasions variability for the peripheral volume of distribution (V3/F(oral)) and clearance (CL/F(oral)) were 18.5 and 19.3%, respectively. A rate constant representing hydrolysis of propacetamol to paracetamol (K(a) 96 h(-1)) was size related, but not age related. The relative bioavailability of intravenous propacetamol compared with an oral elixir was 0.5. CONCLUSIONS: A mean paracetamol serum concentration of 10 mg x l(-1) is achieved in children 2-15 years given a standard dose of propacetamol 30 mg x kg(-1) 6 h. This concentration in the effect compartment is associated with a pain reduction of 2.6/10 after tonsillectomy and provides satisfactory analgesia for mild to moderate pain. Clearance is reduced in children less than 1 year of age and the target concentration of 10 mg x l(-1) may be achieved by scaling this standard dose regimen using predicted clearance in this younger age group.
Acetaminophen↗
No urine, no urinary clearance.
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Acetaminophen↗
Energetics of the sequence-specific binding of single-stranded DNA by the F factor relaxase domain.
Transfer of conjugative plasmids between bacteria requires the activity of relaxases or mobilization proteins. These proteins nick the plasmid in a site- and strand-specific manner prior to transfer of the cut strand from donor to recipient. TraI36, the relaxase domain of TraI from plasmid F factor, binds a single-stranded DNA (ssDNA) oligonucleotide containing an F factor sequence with high affinity and sequence specificity. To better understand the energetics of this interaction, we examined the temperature, salt, and pH dependence of TraI36 recognition. Binding is entropically driven below 25 degrees C and enthalpically driven at higher temperatures. van't Hoff analysis yields an estimated deltaC(P)(0) of binding (-3300 cal x mol(-1) x K(-1)) that is larger and more negative than that observed for most double-stranded DNA (dsDNA)-binding proteins. Based on analyses of circular dichroism data and the crystal structure of the unliganded protein, we attribute the deltaC(P)(0) to both burial of hydrophobic surface area and coupled folding and binding of the protein. The salt dependence of the binding indicates that several ssDNA phosphates are buried in the complex, and the pH dependence of the binding suggests that some of these ssDNA phosphates form ionic interactions with basic residues of the protein. Although data are available for relatively few sequence-specific ssDNA-binding proteins, sufficient differences exist between TraI36 and other proteins to indicate that, like dsDNA-binding proteins, ssDNA-binding proteins use different motifs and combinations of forces to achieve specific recognition.
Anisotropy↗