Prospects for online adaptive radiation therapy (ART) for head and neck cancer.

BACKGROUND: The aim of the present study is to examine the impact of kV-CBCT-based online adaptive radiation therapy (ART) on dosimetric parameters in comparison to image-guided-radiotherapy (IGRT) in consecutive patients with tumors in the head and neck region from a prospective registry. METHODS: The study comprises all consecutive patients with tumors in the head and neck area who were treated with kV-CBCT-based online ART or IGRT-modus at the linear-accelerator ETHOS™. As a measure of effectiveness, the equivalent-uniform-dose was calculated for the CTV (EUDCTV) and organs-at-risk (EUDOAR) and normalized to the prescribed dose. As an important determinant for the need of ART the interfractional shifts of anatomic landmarks related to the tongue were analyzed and compared to the intrafractional shifts. The latter determine the performance of the adapted dose distribution on the verification CBCT2 postadaptation. RESULTS: Altogether 59 consecutive patients with tumors in the head-and-neck-area were treated from 01.12.2021 to 31.01.2023. Ten of all 59 patients (10/59; 16.9%) received at least one phase within a treatment course with ART. Of 46 fractions in the adaptive mode, irradiation was conducted in 65.2% of fractions with the adaptive-plan, the scheduled-plan in the remaining. The dispersion of the distributions of EUDCTV-values from the 46 dose fractions differed significantly between the scheduled and adaptive plans (Ansari-Bradley-Test, p = 0.0158). Thus, the 2.5th percentile of the EUDCTV-values by the adaptive plans amounted 97.1% (95% CI 96.6-99.5%) and by the scheduled plans 78.1% (95% CI 61.8-88.7%). While the EUDCTV for the accumulated dose distributions stayed above 95% at PTV-margins of ≥ 3 mm for all 8 analyzed treatment phases the scheduled plans did for margins ≥ 5 mm. The intrafractional anatomic shifts of all 8 measured anatomic landmarks were smaller than the interfractional with overall median values of 8.5 mm and 5.5 mm (p < 0.0001 for five and p < 0.05 for all parameters, pairwise comparisons, signed-rank-test). The EUDOAR-values for the larynx and the parotid gland were significantly lower for the adaptive compared with the scheduled plans (Wilcoxon-test, p < 0.001). CONCLUSIONS: The mobile tongue and tongue base showed considerable interfractional variations. While PTV-margins of 5 mm were sufficient for IGRT, ART showed the potential of decreasing PTV-margins and spare dose to the organs-at-risk.

S-1 maintenance therapy in Caucasian patients with metastatic esophagogastric adenocarcinoma-final results of the randomized AIO MATEO phase II trial.

PURPOSE: Platinum-fluoropyrimidine combinations are standard of care for treatment of metastatic esophagogastric adenocarcinoma. The optimal duration of first-line chemotherapy is unknown, however, and maintenance strategies have not yet been established. DESIGN: MATEO is an international randomized phase II trial exploring efficacy and safety of S-1 maintenance therapy in human epidermal growth factor receptor 2 (HER2)-negative advanced esophagogastric adenocarcinoma. After 3 months of first-line platinum-fluoropyrimidine-based induction therapy, patients without progression were randomized in a 2 : 1 allocation to receive S-1 monotherapy (arm A) or to continue combination chemotherapy (arm B). The primary objective was to show non-inferiority of overall survival in the S-1 maintenance group. Progression-free survival, adverse events, and quality of life were secondary endpoints. RESULTS: From 2014 to 2019, 110 and 55 patients were randomized in arm A and arm B, respectively (recruitment closed prematurely). Median overall survival from randomization was 13.4 months for arm A and 11.4 months for arm B [hazard ratio 0.97 (80% confidence interval 0.76-1.23), P = 0.86]. Median progression-free survival from randomization was 4.3 and 6.1 months for arm A versus arm B, respectively [hazard ratio 1.10 (80% confidence interval 0.86-1.39), P = 0.62]. Patients in arm A had numerically fewer treatment-related adverse events (84.9% versus 93.9%) and significantly less peripheral sensory polyneuropathy ≥grade 2 (9.4% versus 36.7%). CONCLUSIONS: S-1 maintenance following platinum-based induction therapy leads to non-inferior survival outcomes compared with the continuation of platinum-based combination. Toxicity patterns favor a fluoropyrimidine maintenance strategy. These data challenge the continued use of platinum combination chemotherapy after response to 3 months induction therapy in patients with advanced human epidermal growth factor receptor 2-negative esophagogastric adenocarcinoma.

[Children and Adolescents with Asthma Differ in Lung Function Parameters and Exhaled NO from Children and Adolescents with Obesity]. / Kinder und Jugendliche mit Asthma unterscheiden sich in ihrer Lungenfunktion und im exhalierten NO von Kindern und Jugendlichen mit Adipositas.

BACKGROUND: The prevalence of asthma and overweight/obesity in children and adolescents is continuously increasing over the last decades. It remains unclear if overweight/obesity raises the risk of developing asthma or if an uncontrolled asthma increases the risk of developing overweight/obesity by restricting physical activity. OBJECTIVES: We aimed to elucidate, if children and adolescents with overweight/obesity differ from normal-weight asthmatics in lung functions parameters (FEV1, FEV1/VC, MEF50 and SRtot) and in exhaled nitric oxide (FeNO). METHODS: Totally, n=142 children and adolescents aged 6-18 years were included in this study: group 1 comprised n=44 with overweight/obesity defined as a Body-Mass-Index (BMI)>90th percentile; group 2 n=44 with a doctors diagnosed bronchial asthma according to the GINA-guidelines, and group 3 with n=36 pulmonary healthy controls. N=18 children with both asthma and overweight/obesity were excluded from further analysis. We collected data about socio-demographic variables from a standardized questionnaire, bodyplethysmography (FEV1, FEV1/VC, MEF50 and SRtot) and FeNO. RESULTS: Normal-weight children and adolescents with asthma had significantly lower FEV1/VC (Tiffenau-Index 90,9±12,8) and MEF50 (84.0% predicted±27.6) than children with overweight/obesity (97,6±12,4 p=0.001 respectively 99.1±20.9 p=0.001) and healthy controls (98±13,5 p=0,003; 96.7±19.3 p=0.011). Normal weight asthmatics had a significantly higher FeNO (38.3 ppb) than children and adolescents with overweight/obesity (14.0 ppb p=0.014). CONCLUSIONS: Normal-weight children and adolescents with asthma differ significantly both in their lung function parameters as well as in their exhaled nitric oxide concentration from children and adolescents with overweight/obesity. For clinical practice it is important to note that children and adolescents with overweight/obesity have no signs of an obstructive airway diseases and are as resilient as healthy children and adolescents with regard to their lung function. The possible late-onset of asthma symptoms and lung function changes in children and adolescents with overweight/obesity requires further detailed longitudinal studies.

Enhancing the care of women with rheumatic diseases during pregnancy: challenges and unmet needs in the Middle East.

Pregnancy in women with rheumatic disorders is known to be associated with risks for both the mother and fetus; however, these risks can be minimized with proper planning and careful management of the disease. In the Middle East, there are specific cultural challenges that may have a negative impact on the care that women with rheumatic disorders receive. There is a need for cross-collaboration between specialist physicians, improved awareness of rheumatic disorders among the general public and more open discussion with patients about the potential complications of pregnancy. Women in the region are often unwilling to discuss their disease with their partner and are even less likely to seek advice regarding family planning from their physician. The objective of this review is to highlight the specific challenges of pregnancy management and to discuss why establishing specialist pregnancy clinics for women with rheumatic disorders could be an effective solution. Such clinics can provide high quality care before, during and after pregnancy as shown in several European and US centers. Additionally, such clinics could be useful for the collection of pregnancy outcomes data from the Middle East, which may currently be lacking in the region, in order to highlight where further improvements can be made. With specialist care and analysis of pregnancy outcomes, the standard of care for women with rheumatic disorders in this area could be significantly improved.

Prevalence of angiotensin-converting enzyme gene insertion-deletion polymorphism in patients with primary knee osteoarthritis.

OBJECTIVE: Angiotensin converting enzyme (ACE) plays an important role in a number of inflammatory and immune related disorders. This study was undertaken to investigate an association between Angiotensin converting enzyme (ACE) gene insertion- deletion (I/D) polymorphism and primary knee osteoarthritis (OA) in Kuwait and to explore a correlation between clinical subgroups of OA and ACE I/D polymorphism genotypes. PATIENTS AND METHODS: The prevalence of ACE gene I/D polymorphism was determined in 115 patients with primary knee OA and 111 ethnically matched healthy controls by using polymerase chain reaction (PCR) of the genomic DNA. The association of ACE gene I/D polymorphism genotypes was also studied with age of disease onset, function and radiological grading. RESULTS: No significant difference was detected in the frequency of ACE gene I/D polymorphism genotypes and alleles between knee OA patients and the controls. The frequency of ACE gene polymorphism genotypes was also studied in subgroups on the basis of clinical parameters of age of onset of disease, function and radiological grading and no significant difference was detected between subgroups of OA patients and the controls. This is in sharp contrast to a previous report from Korea in which a significant association has been reported between ACE gene polymorphism and knee OA. CONCLUSION: This study did not find an association between ACE gene I/D polymorphism genotypes in Kuwaiti patients with primary knee osteoarthritis and the onset or severity of the disease, which is very different from Korean knee OA patients in which an association has been reported.

Subthreshold membrane-potential resonances shape spike-train patterns in the entorhinal cortex.

Many neurons exhibit subthreshold membrane-potential resonances, such that the largest voltage responses occur at preferred stimulation frequencies. Because subthreshold resonances are known to influence the rhythmic activity at the network level, it is vital to understand how they affect spike generation on the single-cell level. We therefore investigated both resonant and nonresonant neurons of rat entorhinal cortex. A minimal resonate-and-fire type model based on measured physiological parameters captures fundamental properties of neuronal firing statistics surprisingly well and helps to shed light on the mechanisms that shape spike patterns: 1) subthreshold resonance together with a spike-induced reset of subthreshold oscillations leads to spike clustering and 2) spike-induced dynamics influence the fine structure of interspike interval (ISI) distributions and are responsible for ISI correlations appearing at higher firing rates (> or =3 Hz). Both mechanisms are likely to account for the specific discharge characteristics of various cell types.

Angiotensin-converting enzyme gene polymorphism in Kuwaiti patients with systemic lupus erythematosus.

OBJECTIVE: To investigate the frequency of angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism genotypes in patients with systemic lupus erythematosus (SLE), and to study the correlation between I/D polymorphism of the ACE gene and the clinical manifestations of SLE, especially vascular involvement, lupus nephritis and disease severity. METHODS: The frequency of ACE gene I/D polymorphism genotypes was determined in 92 patients with SLE from Kuwait, and compared to that in 100 ethnically matched healthy controls using the polymerase chain reaction. RESULTS: The distribution of ACE I/D polymorphism and allele frequencies in SLE patients was not significantly different from controls. Further analyses of SLE patients showed that there was a significant association between DD genotype and Raynaud's phenomenon (p=0.008, odd ratio=5.4, 95% confidence interval: 1.6-18.6). However, there was no significant association between the ACE genotype and lupus nephritis or disease severity. CONCLUSION: No difference was found between the distribution of the ACE genotype in SLE patients and the general pop-ulation in Kuwait. However, the presence of the DD genotype may confer susceptibility to the development of vascular morbidity.

Renal complications associated with human parvovirus B19 infection in early childhood.

A previously healthy two-year-old girl presented with proteinuria and macroscopic haematuria. Laboratory findings included haemolytic anaemia with thrombocytopenia. Interestingly, continuing reticulocytopenia was noted. Therefore an acute parvovirus B19 infection was suspected, which could be confirmed by serological and molecularbiological evidence. This case report underlines renal complications of parvovirus B19 infection in early childhood including haemolytic-uraemic syndrome (HUS)-like episodes, and potential pathogenetic mechanisms are discussed.

Dynamics of rat entorhinal cortex layer II and III cells: characteristics of membrane potential resonance at rest predict oscillation properties near threshold.

Neurones generate intrinsic subthreshold membrane potential oscillations (MPOs) under various physiological and behavioural conditions. These oscillations influence neural responses and coding properties on many levels. On the single-cell level, MPOs modulate the temporal precision of action potentials; they also have a pronounced impact on large-scale cortical activity. Recent studies have described a close association between the MPOs of a given neurone and its electrical resonance properties. Using intracellular sharp microelectrode recordings we examine both dynamical characteristics in layers II and III of the entorhinal cortex (EC). Our data from EC layer II stellate cells show strong membrane potential resonances and oscillations, both in the range of 5-15 Hz. At the resonance maximum, the membrane impedance can be more than twice as large as the input resistance. In EC layer III cells, MPOs could not be elicited, and frequency-resolved impedances decay monotonically with increasing frequency or has only a small peak followed by a subsequent decay. To quantify and compare the resonance and oscillation properties, we use a simple mathematical model that includes stochastic components to capture channel noise. Based on this model we demonstrate that electrical resonance is closely related though not equivalent to the occurrence of sag-potentials and MPOs. MPO frequencies can be predicted from the membrane impedance curve for stellate cells. The model also explains the broad-band nature of the observed MPOs. This underscores the importance of intrinsic noise sources for subthreshold phenomena and rules out a deterministic description of MPOs. In addition, our results show that the two identified cell classes in the superficial EC layers, which are known to target different areas in the hippocampus, also have different preferred frequency ranges and dynamic characteristics. Intrinsic cell properties may thus play a major role for the frequency-dependent information flow in the hippocampal formation.

Musculoskeletal pain, disability and health-seeking behavior in adult Kuwaitis using a validated Arabic version of the WHO-ILAR COPCORD Core Questionnaire.

OBJECTIVE: The WHO-ILAR Community Oriented Program for Control of Rheumatic Diseases (COPCORD) primarily aims to estimate the burden of musculoskeletal symptoms/disorders. We investigated data on musculoskeletal pain, disability and health-seeking behavior in the first community-based COPCORD study in Kuwait. METHODS: The validated Arabic version of the WHO-ILAR COPCORD Core Questionnaire was used in 2,500 randomly selected Kuwaiti households. The target population comprised Kuwaiti nationals aged 15 years and older. Twenty-four trained field workers completed the survey in 8 weeks. Those subjects reporting musculoskeletal pain were identified (Phase 1), and were asked to complete a self-evaluation questionnaire (Phase 2) prior to rheumatological examination (Phase 3). Phase 2 included questions on the site and severity of pain, traumatic events, functional disability, and treatment. Patients marked their pain sites on a mannequin during their interviews. "Sufferers" were defined as those with musculoskeletal pain and no history of trauma. RESULTS: A total of 7,670 adults were interviewed (response rate 88%), of whom 2,057 had musculoskeletal pain not related to trauma. Knees, back, and shoulders were the common sites of pain. Most of the sufferers reported the severity of pain as being moderate to severe. Functional disability was reported in 39.1% of the sufferers. The age-sex population adjusted prevalence rate for musculoskeletal pain was 35.7% in females and 20.2% in males. The most common sources for advice on treatment were physicians in hospitals (68.8%) and general practitioners (30.4%). 82% had prescriptions for their medications, while 19.4% had self prescribed tablets. CONCLUSION: Musculoskeletal pain is a major health problem among Kuwaitis and deserves intense government attention.

Representation of acoustic communication signals by insect auditory receptor neurons.

Despite their simple auditory systems, some insect species recognize certain temporal aspects of acoustic stimuli with an acuity equal to that of vertebrates; however, the underlying neural mechanisms and coding schemes are only partially understood. In this study, we analyze the response characteristics of the peripheral auditory system of grasshoppers with special emphasis on the representation of species-specific communication signals. We use both natural calling songs and artificial random stimuli designed to focus on two low-order statistical properties of the songs: their typical time scales and the distribution of their modulation amplitudes. Based on stimulus reconstruction techniques and quantified within an information-theoretic framework, our data show that artificial stimuli with typical time scales of >40 msec can be read from single spike trains with high accuracy. Faster stimulus variations can be reconstructed only for behaviorally relevant amplitude distributions. The highest rates of information transmission (180 bits/sec) and the highest coding efficiencies (40%) are obtained for stimuli that capture both the time scales and amplitude distributions of natural songs. Use of multiple spike trains significantly improves the reconstruction of stimuli that vary on time scales <40 msec or feature amplitude distributions as occur when several grasshopper songs overlap. Signal-to-noise ratios obtained from the reconstructions of natural songs do not exceed those obtained from artificial stimuli with the same low-order statistical properties. We conclude that auditory receptor neurons are optimized to extract both the time scales and the amplitude distribution of natural songs. They are not optimized, however, to extract higher-order statistical properties of the song-specific rhythmic patterns.

Simple, sensitive, and specific detection of human immunodeficiency virus type 1 subtype B DNA in dried blood samples for diagnosis in infants in the field.

The detection of virus is used to diagnose human immunodeficiency virus type 1 (HIV-1) infection in infants due to the persistence of maternal antibodies for a year or more. An HIV-1 DNA PCR assay with simple specimen collection and processing was developed and evaluated. Whole blood was collected on filter paper that lysed cells and bound the DNA, eliminating specimen centrifugation and extraction procedures. The DNA remained bound to the filter paper during PCR amplification. Assays of copy number standards showed reproducible detection of 5 to 10 copies of HIV-1 in 5 microl of whole blood. The sensitivity of the assay did not decrease after storage of the standards on filter paper for 3 months at room temperature or after incubation at 37 or 45 degrees C for 20 h. The primers used for nested PCR of the HIV-1 pol gene amplified templates from a reference panel of multiple HIV-1 subtypes but did not amplify a subtype A or a subtype C virus from children living in Seattle. The assay had a sensitivity of 98.4% and a specificity of 98.3% for testing of 122 specimens from 35 HIV-1-infected and 16 uninfected children and 43 seronegative adults living in Washington. The assay had a sensitivity of 99% and a specificity of 100% for testing of 102 HIV-1-positive (as determined by enzyme immunoassay) Peruvian women and 6 seropositive and 34 seronegative infants. This assay, with adsorption of whole blood to filter paper and no specimen processing, provides a practical, economical, sensitive, and specific method for the diagnosis of HIV-1 subtype B infection in infants.

Suppression of maternal virus load with zidovudine, didanosine, and indinavir combination therapy prevents mother-to-fetus HIV transmission in macaques.

Recently, we developed a maternal-fetal macaque model using a highly pathogenic HIV-2 strain, HIV-2287, to study the time course of HIV transmission in utero. Most pregnant macaques (Macaca nemestrina) infected with HIV-2287 (10-103 infective doses) transmitted HIV to their fetuses, as verified by positive identification of virus-infected mononuclear cells and free viral RNA in fetal blood. To determine whether an antiretroviral drug combination therapy composed of two dideoxynucleosides, azidothymidine (15 mg/kg) and dideoxyinosine (15 mg/kg), and a protease inhibitor, indinavir (25 mg/kg), could completely inhibit mother-to-fetus HIV transmission, we administered these drugs orally through gastric catheters to five pregnant macaques infected with 10 infective doses of HIV-2287. Beginning 30 minutes after HIV inoculation, the dams were given the combination antiviral therapy three times daily until delivery by cesarean section. Drug treatment reduced the maternal virus load to a minimally detectable level but did not prevent primary HIV-2287 infection. All fetal and infant blood samples were virus negative by internally controlled RNA polymerase chain reaction (QC-RNA-PCR) and virus coculture assays. Fetal and infant CD4+ T-cell levels remained normal throughout the experiment. These findings strongly suggest that combination chemotherapy with azidothymidine, dideoxyinosine, and indinavir can suppress maternal viral load enough to prevent mother-to-fetus transmission of HIV.

Opioid reward mechanisms: a key role in drug abuse?

There is increasing evidence to implicate the mesolimbic dopamine system in the rewarding effects of drugs of abuse such as opioids, psychostimulants, and alcohol, and in addition endogenous opioids may play a key role in the underlying adaptive mechanisms. Opioid agonists with affinity for mu and delta opioid receptors are rewarding, whereas opioid agonists with affinity for kappa receptors are aversive. These opposing motivational effects are paralleled by an increase and decrease, respectively, of dopamine release in the nucleus accumbens. Opposite effects are induced in response to selective antagonists for these different receptor types, pointing to tonically active endogenous opioid reward mechanisms. Withdrawal from chronic morphine results in sensitization for opioid reward; an effect that is counteracted by kappa opioid agonists. The rewarding effects of psychostimulants such as cocaine and amphetamine, mediated by the mesolimbic dopamine pathway, are modulated by opioid mechanisms in both directions: sensitization by morphine pretreatment, inhibition by kappa receptor agonists. A modulatory role of endogenous opioids is also suggested from biochemical data, showing increased dynorphin and kappa receptor expression after chronic cocaine treatment. Alcohol reward involves the mesolimbic reward system also, and opioids modulate this behaviour. Naltrexone as well as selective mu and delta opioid receptor antagonists decrease alcohol consumption in operant conditioning models. Biochemical approaches point to a functional deficit of endogenous opioids in genetic models exhibiting high prevalence for alcohol intake. The therapeutic implications of these data are discussed.

Neural codes: firing rates and beyond.

Computational neuroscience has contributed significantly to our understanding of higher brain function by combining experimental neurobiology, psychophysics, modeling, and mathematical analysis. This article reviews recent advances in a key area: neural coding and information processing. It is shown that synapses are capable of supporting computations based on highly structured temporal codes. Such codes could provide a substrate for unambiguous representations of complex stimuli and be used to solve difficult cognitive tasks, such as the binding problem. Unsupervised learning rules could generate the circuitry required for precise temporal codes. Together, these results indicate that neural systems perform a rich repertoire of computations based on action potential timing.

Endogenous opioid systems and alcohol addiction.

Alcohol exerts numerous pharmacological effects through its interaction with various neurotransmitters and neuromodulators. Among the latter, the endogenous opioids play a key role in the rewarding (addictive) properties of ethanol. Three types of opioid receptors (mu, delta and kappa) represent the respective targets of the major opioid peptides (beta-endorphin, enkephalins and dynorphins, respectively). The rewarding (reinforcing) properties of mu- and delta-receptor ligands are brought by activation of the mesolimbic dopamine system which ascends from the ventral tegmentum of the midbrain (VTA) to rostral structures; of these, the nucleus accumbens (NAC) is of particular importance in drug addiction. In contrast, dysphoria results from activation of kappa-receptors. The neurochemical manifestations of these opposing effects are, respectively, increases and decreases in dopamine release in the NAC. Several lines of evidence indicate that alcohol interferes with endogenous opioid mechanisms which are closely linked with dopamine transmission in the mesolimbic pathway. The view that condensation products of dopamine and alcohol-derived aldehyde (tetrahydroisoquinolines) play a role remains controversial. There is, however, much information on the direct (acute and chronic) effects of alcohol on the binding properties of opioid receptors, as well as modulation of opioid peptide synthesis and secretion (e.g. a suggested increase in beta-endorphin release). In view of the reinforcing properties of alcohol, it is relevant to consider behavioural studies involving alcohol self-administration in rodents and primates. Low doses of morphine have been found to increase, and higher doses of the opiate to decrease, alcohol consumption. Conversely, opioid antagonists such as naloxone and naltrexone (which bind to non-selectively opioid receptors) have been shown to decrease alcohol consumption under various experimental conditions. Similar results have been reported when selective mu- or delta-receptor antagonists are administered. Results obtained in genetic models of high preference for alcohol also support the view that alcohol intake depends on the activity of the endogenous opioid reward system and that alcohol consumption may serve to compensate for inherent deficits in this system. One hypothetical model proposes that reward results from activation of mu-opioid receptors in the VTA and/or delta-receptor in the NAC; both these nuclei are targets of endogenous beta-endorphin. It is suggested that alcohol interferes with this reward pathway either directly or indirectly. The available experimental data accord well with those obtained from clinical studies which opioid antagonists have been used to prevent relapse in alcoholics. Conceptual considerations concerning communalities between various forms of addictions are also discussed in this review.

Viral dynamics in vivo: limitations on estimates of intracellular delay and virus decay.

Anti-viral drug treatment of human immunodeficiency virus type I (HIV-1) and hepatitis B virus (HBV) infections causes rapid reduction in plasma virus load. Viral decline occurs in several phases and provides information on important kinetic constants of virus replication in vivo and pharmacodynamical properties. We develop a mathematical model that takes into account the intracellular phase of the viral life-cycle, defined as the time between infection of a cell and production of new virus particles. We derive analytic solutions for the dynamics following treatment with reverse transcriptase inhibitors, protease inhibitors, or a combination of both. For HIV-1, our results show that the phase of rapid decay in plasma virus (days 2-7) allows precise estimates for the turnover rate of productively infected cells. The initial quasi-stationary phase (days 0-1) and the transition phase (days 1-2) are explained by the combined effects of pharmacological and intracellular delays, the clearance of free virus particles, and the decay of infected cells. Reliable estimates of the first three quantities are not possible from data on virus load only; such estimates require additional measurements. In contrast with HIV-1, for HBV our model predicts that frequent early sampling of plasma virus will lead to reliable estimates of the free virus half-life and the pharmacological properties of the administered drug. On the other hand, for HBV the half-life of infected cells cannot be estimated from plasma virus decay.