Accurate model predicting sustained response at week 4 of therapy with pegylated interferon with ribavirin in patients with chronic hepatitis C.

Current models used to predict response to peginterferon plus ribavirin treatment, based on viral decline during the first 12 weeks of therapy, have focused on creating an early stopping rule to avoid unnecessary prolongation of therapy. We developed a multivariate model that predicted sustained virological response and nonresponse at baseline and during the first 12 weeks of therapy using collected data from 186 unselected patients with chronic hepatitis C treated with peginterferon plus ribavirin. This model employed ordinal regression with similarity least squares technology to assign the probability of a given outcome. Model variables include sex, age, prior treatment status, genotype, baseline serum alanine aminotransferase levels, histologic necroinflammation and fibrosis scores and serum hepatitis C virus RNA concentration at baseline and weeks, 4, 8, and 12. A multivariate model demonstrated high performance values at all time points. At baseline, the model demonstrated a negative predictive value (NPV) and a positive predictive value (PPV) of 91% and 95%, respectively. At week 4, these values improved to 97% and 100%, respectively, with 95% sensitivity, 89% specificity and 93% accuracy. At week 4, the model was equally efficient for naïve or previously treated patients. Internal validation demonstrated 90% PPV, 94% NPV, 95% sensitivity, 88% specificity and 92% accuracy. A week 4 stopping rule for patients with chronic hepatitis C treated with peginterferon with ribavirin might be proposed by using the model developed in our study.

Intrinsic proportions of the human tarsus: an original approach to tarsal biometry.

Few precise biometrical data on human tarsal bones are available, and those published consist principally of linear and angular measurements made on dried bones or on radiographs. The material consisted of 86 complete adult human tarsi (dried bones). The tarsal proportions were determined using the relative tarsal weights (Weight of each of the seven tarsal bones/Weight of the total tarsusx100). The calcaneus was the greatest tarsal bone (41.95%), and the talus the second-largest (28.45%). The medial cuneiform, the cuboid, and the navicular had very similar proportions (7.00-8.38%), as did the intermediate and lateral cuneiforms (2.98% and 3.81%). The study of the ranks of each bone by decreasing proportion allowed the determination of individual variability. The posterior tarsal row was considerably larger (70.40%) than the anterior row (29.60%), resulting in an antero-posterior ratio of 0.42. The medial and lateral tarsal columns had quite similar proportions (50.63% and 49.37%), resulting in a latero-medial ratio of 0.98. The intrinsic tarsal proportions are fundamental biometrical data which seem to be of interest for a better characterization of the human foot in clinical practice and for quantitative approaches in functional and comparative morphology and in paleontology.

Sexual dimorphism of the human mandible: demonstration by elliptical Fourier analysis.

A new quantitative approach of the mandibular sexual dimorphism, based on computer-aided image analysis and elliptical Fourier analysis of the mandibular outline in lateral view is presented. This method was applied to a series of 117 dentulous mandibles from 69 male and 48 female individuals native of Rhenish countries. Statistical discriminant analysis of the elliptical Fourier harmonics allowed the demonstration of a significant sexual dimorphism in 97.1% of males and 91.7% of females, i.e. in a higher proportion than in previous studies using classical metrical approaches. This original method opens interesting perspectives for increasing the accuracy of sex identification in current anthropological practice and in forensic procedures.

[Augustin Belloste (1654-1730), aspects of the surgery in military hospitals during the Piemont-Savoie War (1686-96)]. / Augustin Belloste (1654-1730), aspects de la chirurgie militaire hospitaliére pendant la guerre de Piémont-Savoie (1686-96).

The surgical practice in military hospitals during the XVIIth century remains poorly known. An original statement is provided by A. Belloste (1654-1730) who enlisted as military surgeon in 1686. In 1690 began the Piemont-Savoie War during which he was in position in the military hospitals of Briançon, Pignerol, and Oulx. In 1696, after the end of the war, A. Belloste published a treatise, the hospital surgeon, written according to the experience he gained and the observations he consigned during his ten years of practice, particularly in the military hospital of Briançon. Interesting information is given concerning the military hospitals recruitment and the patients origins. The transfer to a military hospital seemed to be considered as the last resort, with sometimes wounded persons waiting during long months in dreadful conditions. The pathologies observed and treated consisted principally in war traumatisms by sword or firearms, but also came victims of traumatisms happened during great defensive works as those of Vauban, or presenting pathologies related to the specificites of the alpine environment as falls, altitude or cold... The lodging conditions in hospital were summary, and were often unfavourable to a good evolution of the injuries. A. Belloste particularly developed and defended the interest of a soft, measured, and rational treatment of the wounds.

Relative weights of the human carpal bones: biological and functional interests.

The relative carpal weights (Weight of each of the eight carpal bones/Weight of the complete carpus x 100) were studied in a series of 95 complete human adult carpi (dried bones). The greatest was the capitatum (19.92%; mean rank 1.16) and the smallest the pisiform (4.43%; mean rank 8.00). The scaphoideum and the hamatum presented very near values (17.19 and 15.81%; mean ranks 2.34 and 2.74), as did the lunatum and trapezium (12.56 and 12.52%; mean ranks 4.41 and 4.48), and the triquetrum and trapezoideum (9.21 and 8.36%; mean ranks 6.19 and 6.68). Within the proximal row, a regular radio-ulnar decrease was observed from the scaphoideum (39.58%) to the pisiform (10.20%). Within the distal row, a marked break existed between the trapezoideum (14.77%) and the capitatum (35.19%); the capitato-hamatal element represented 63.11% of the distal row. The distal row (mean 56.61%) was always a little heavier than the proximal row (mean 43.39%), resulting in a mean proximo-distal weight ratio of 0.77. A radio-ulnar decrease in the relative weights was observed from the radial to the ulnar carpal columns. The determination of the relative carpal weights is simple, reproducible, non-invasive, rapid, and inexpensive, and can be considered an interesting and valuable approach to the estimation of the relative carpal volumes. Relative carpal weights reveal the intrinsic proportions of the carpus and are the reflection of biological, functional and evolutionary constraints. Interesting relations appear with carpal growth and ossification, with functional characteristics, and with evolutionary processes.

Assessment of hepatitis C virus RNA stability in serum by the Quantiplex branched DNA assay.

OBJECTIVES: Quantification of hepatitis C virus (HCV) RNA in serum is used to assess the probability of treatment response and to monitor antiviral therapy. Since serum specimens often are shipped to central sites for HCV RNA testing, it is important to define conditions that preserve HCV RNA integrity. METHODS: We evaluated the stability of HCV RNA in 25 previously frozen (PF) and 11 fresh, never previously frozen (NPF) specimens subjected to handling and short-term storage conditions that mimic those encountered during interlaboratory shipping. All sera were separated within 4 h of collection. PF samples covering a approximately 3 log10 HCV RNA dynamic range were thawed, divided into aliquots, incubated at 4, 23, and 37 degrees C (+/- 1.5 degrees C) for 24, 48, 72 and 96 h (+/- 2 h), and then refrozen at -70 degrees C prior to testing with the Quantiplex HCV RNA 2.0 assay. Eleven NPF samples were stored at -70, -20, and 4 degrees C (+/- 1.5 degrees C) for up to 1 month prior to testing. RESULTS: Linear regression analysis showed no HCV RNA degradation in PF specimens kept at 4 degrees C over 4 days. However, HCV RNA levels in PF specimens decreased over 4 days by 20 and 105% at 23 and 37 degrees C, respectively. Three independent statistical methods showed that the probability of specimen failure in PF specimens, defined as a loss of 20% or more of HCV RNA, was lowest at 4 degrees C and increased with increasing temperature. The HCV RNA quantification of the 11 NPF specimens stored at 4 degrees C was similar to their frozen controls. CONCLUSION: HCV RNA in separated serum specimens is stable for at least 4 days at 4 degrees C.

Congenital absence of the lateral metatarso-phalangeal sesamoid bone of the human hallux: a case report.

A case of congenital absence of the lateral metatarsophalangeal sesamoid bone of the hallux is reported, in a 47-year-old woman. The lateral sesamoid bone was absent on the right hallux, and extremely reduced on the left hallux. The normal intersesamoidean crest and both sesamoidean grooves of the metatarsal head were absent. Physical examination was normal, and no functional disturbance resulted from this variant. Only two previous cases have been found in the literature. It must be distinguished from a total resorption due to an infectious process, or from an absence due to surgical excision. This absence can be related to the general tendency of disappearance of the sesamoid bones within hominoid primates.

Shape of the orbital opening: individual characterization and analysis of variability in modern humans, Gorilla gorilla, and Pan troglodytes.

The description of the human orbital shape is principally qualitative in the classical literature, and characterised by adjectives such as circular, rectangular or quadrangular. In order to provide a precise quantification and interpretation of this shape, a study based on automatic image analysis and Fourier analysis was carried out on 45 human skulls (30 males, 15 females), and for comparison on 61 skulls of Gorilla gorilla (40 males, 21 females), and 34 skulls of Pan troglodytes (20 males, 14 females). Sexual dimorphism in the shape of the orbital opening was not demonstrated. Its dominant morphological features could be characterized by Fourier analysis; elliptical elongation and quadrangularity were dominant morphological features of the shape of the orbital opening in the three species. Elliptical elongation was more marked in humans and Pan, whereas quadrangularity was particularly emphasized in Gorilla. An intraspecific variability of the shape of the orbital opening existed in humans, Gorilla and Pan, and seemed close in the three species. Interspecific partition between humans, Gorilla and Pan was demonstrated despite the variability observed in the three species studied. Interspecific differences between Gorilla and the Pan-humans group were principally explained by the differences in quadrangularity, and by differences in orientation of triangularity and pentagonality. Differences in the shape of the orbital opening between humans and Pan were principally explained by differences in hexagonality, and by differences in orientation of quadrangularity. A closeness of shape between some humans and some individuals in Pan and, to a lesser degree, with some individuals in Gorilla was observed, demonstrating the existence of a morphological continuum of the shape of the orbital opening in hominoids.

Effect of multiple freeze-thaw cycles on hepatitis B virus DNA and hepatitis C virus RNA quantification as measured with branched-DNA technology.

Quantification of hepatitis B virus (HBV) DNA and hepatitis C virus (HCV) RNA often is performed in specimens that have been frozen and thawed more than once. To ensure optimal therapeutic and prognostic value, it is important to establish whether viral load measurements are affected by repeated freeze-thaw (FT) cycles. We therefore evaluated the effect of multiple FT cycles on HBV DNA and HCV RNA quantification by testing serum specimens subjected to one (baseline), two, four, and eight FT cycles with the appropriate Chiron Quantiplex assay. Linear regression analysis showed minor increases of 1.7% per FT cycle for both HBV DNA and HCV RNA. The rise in HCV RNA levels was more pronounced among low-concentration samples, since further analysis revealed an increase of 3.2% per FT cycle among samples with 0.2 to 3.86 Meq of HCV RNA per ml. Given that the coefficient of variation for the Quantiplex assays is generally 10 to 15%, the minor increases in HBV DNA and HCV RNA levels with progressive FT cycles for the specimens tested were recognized only because analysis of variance revealed a statistically significant trend (P < 0.05). Due to the minor statistical trend, the clinical impact for individual patient specimens is likely to be limited, but it may deserve further study. In conclusion, the concentration of HBV DNA and HCV RNA in serum specimens subjected to up to eight short-term FT cycles was stable.

Importance of elliptic Fourier methods for morphometry of complex outlines: application to the distal human femur.

The purpose of this technical note is to present an automatic procedure of shape characterisation using new developments in elliptical Fourier methods combined with image analysis techniques. It was applied, as an example, to the outline of the distal extremity of the distal human femur in inferior axial view. This outline was automatically extracted and characterised by an ordered series of harmonics, each harmonic being described by four new parameters called elliptical descriptors. Step by step reconstructions of outlines using an increasing number of harmonics were than performed. The simultaneous study of the elliptic descriptors and of the step by step reconstructions allowed a considerably easier geometric and morphologic interpretation of the harmonic contributions than classically. The main morphologic features of the distal femur (lateral and medial condyles, intercondylar fossa, lateral and medial borders of the articular surface, and patellar groove) were mainly described by the first seven harmonics. These new developments in elliptic Fourier methods open interesting perspectives for the study of complex outlines, providing an accurate individual morphologic characterisation, and thus the possibility of polymorphic analysis.

Shape of the piriform aperture in Gorilla gorilla, Pan troglodytes, and modern Homo sapiens: characterization and polymorphism analysis.

By using new methodologies based on automatic image analysis, the shape of the piriform aperture was analyzed in Gorilla gorilla (33 males, 13 females), Pan troglodytes (35 males, 22 females), and modern Homo sapiens (30 males, 12 females). The determination of the piriform aperture index (breadth/height) allowed the authors to demonstrate a marked elongation of the aperture in Homo compared with Gorilla and Pan. Individual characterization of the shape was possible with great precision and without ambiguity by using Fourier analysis. An absolute, interspecific partition between Gorilla, Pan, and Homo resulted from the canonical discriminant analysis of the Fourier descriptors. However, a closeness of shape between some individuals in Pan and some in Gorilla and Homo was observed, demonstrating a morphological continuum of the shape of the piriform aperture in hominoids: Pan was in intermediate position between Gorilla and Homo. Interspecific differences between Homo and the group Pan-Gorilla were explained principally by the differences in elongation (amplitude of the second harmonic) and pentagonality (amplitude of the fifth harmonic) and by differences in orientation of quadrangularity (phase of the fourth harmonic). Differences in the shape of the piriform aperture between Pan and Gorilla were explained by differences in orientation of elongation (phase of the second harmonic) and by differences in the component of triangularity (amplitude of the third harmonic). In Gorilla and Pan, the little, elongated, and relatively trapezoidal piriform aperture seems to be a shared primitive feature (plesiomorphic), whereas an elongated piriform aperture seems to be a characteristic and derived feature (apomorphic) of modern Homo sapiens.

Statistical models for predicting a beneficial response to interferon-alpha in patients with chronic hepatitis B.

Therapy with interferon-alpha has been reported to induce remissions in 35% of patients with chronic hepatitis B. The ability to identify patients likely to respond would be helpful in making recommendations for treatment. In this statistical analysis we included 82 patients with chronic hepatitis B who received interferon-alpha in clinical trials at the National Institutes of Health between 1984 and 1991. A response was defined as the loss of hepatitis B virus (HBV) DNA and hepatitis B e antigen (HBeAg) within 1 year of therapy. Multiple clinical parameters measured at pretreatment (month 0) and after the first month (month 1) of therapy were selected by stepwise regression to support the development of the prognostic models: the two-stage logistic regression model and a neural network that utilized higher-order non-linear interactions between variables. Among the 82 patients, 24 (29%) were responders. The two-stage logistic model using pretreatment variables: sex, hepatic fibrosis and alanine aminotransferase (ALT) levels correctly identified 61% of responders and 76% of non-responders. When HBV DNA at month 1 along with sex, initial ALT and fibrosis was included, the resultant model correctly identified 69% of responders and 77% of non-responders. The neural network, by incorporating interactions between variables, correctly identified 77% and 86% of responders, and 87% and 92% of non-responders, using pretreatment factors alone and the combination of pretreatment and month 1 factors respectively. Hence, the neural network was more accurate than the simple logistic regression model in predicting a response to interferon-alpha in chronic hepatitis B. The universality of these models needs to be further verified.

Assessment of hepatitis B virus DNA stability in serum by the Chiron Quantiplex branched-DNA assay.

Quantification of hepatitis B virus (HBV) DNA in serum is used to establish eligibility for treatment and to monitor therapeutic response. With the trend toward centralized testing, defining the conditions that preserve sample integrity is of paramount importance. We therefore evaluated the stability of HBV DNA in 26 previously frozen (PF) and 5 fresh, never previously frozen serum specimens. PF specimens, covering a 3-log10 HBV DNA dynamic range, were thawed and stored at -70, 4, 23, 37, and 45 degrees C (+/-1.5 degrees C) for 0, 24, 72, and 120 h (+/-2 h) and were refrozen at -70 degrees C prior to testing. Five fresh specimens were split into two groups. Both group FG1 and group FG2 specimens were handled as described above; however, group FG1 specimens were subsequently maintained at 4 degrees C and were never frozen prior to testing. Linear regression analysis of PF specimens demonstrated no significant HBV DNA degradation at < or =4 degrees C over 5 days; however, HBV DNA levels decreased by 1.8, 3.4, and 20% per day at 23, 37, and 45 degrees C, respectively. Three independent statistical methods confirmed that the probability of specimen failure, defined as a loss of 20% or more of HBV DNA and/or coagulation of serum, was lowest at < or =4 degrees C and increased with temperature. Because only 10 to 20% of individual patient specimens demonstrated losses of HBV DNA of > or =20% at 23 or 37 degrees C, sufficient numbers of serum specimens must be evaluated to determine overall statistical trends. In conclusion, HBV DNA integrity in separated serum specimens is preserved for at least 5 days when the specimens are stored at -70 or 4 degrees C.

New approaches to human facial morphology using automatic quantification of the relative positions of the orbital and nasal apertures.

The purpose of this study was to define and quantify the relative positions of the orbital and nasal apertures in the human face. The material consisted of 44 skulls (32 males, 12 females). For each skull, an image of the projection of the face was captured perpendicular to the palatal plane, using a CCD camera. The orbital and nasal apertures were segmented and characterized using classical image analysis procedures. New quantitative parameters were automatically determined from the centres of area of the facial apertures, and from horizontal and vertical lines of reference. Sexual differences were only significant for orbital height, nasal height, and orbitonasal height. A medio-lateral orbitonasal overlap, as well as a vertical orbitonasal overlap, existed in all individuals; the vertical overlap was always much more marked than the medio-lateral overlap. Significant proportions of the human face were also demonstrated: on average, the interorbital breadth corresponded to a fifth of the biorbital breadth, and thus to half of the mean orbital breadth; the nasal breadth corresponded to one fourth of the biorbital breadth, and the vertical orbitonasal overlap to one fourth of the orbitonasal height. Some instructive significant correlations were observed between these new parameters. The applications of the present methodology seem of great potential interest in anthropology and clinical biometry.

The retrotransverse foramen of the human atlas vertebra. A distinctive variant within primates.

The occurrence of a retrotransverse foramen of the atlas has been investigated in a series of 409 nonhuman primates representative of 40 genera, and in a series of 500 human atlases (dried bones). In nonhuman primates, no retrotransverse foramen was found in any of the individuals studied. In humans, the retrotransverse foramen was observed in 71 cases (14.2%). It was present bilaterally in 21 cases (29.6% of the 71 foramina), and unilaterally in 50 cases (70.4%). The foramen was present in 44 cases on the right side, and 48 on the left side. The character was noted as present only if it was complete; partial forms were not recorded. Various aspects of the retrotransverse foramen were observed. The present observations suggest that the retrotransverse foramen is a uniquely derived trait (autapomorphy) within primates which is restricted to some individuals in Homo sapiens. Appearance of this foramen in human evolution can be related to the acquisition of the erect posture and bipedal locomotion, and consecutive modifications of the regional venous circulation.

Analysis of clinical data using neural nets.

Clinical studies investigate the interdependence of dosing regimen, efficacy, and side effects. These relationships often involve complex dynamical functions. The study of phenomena intermediate between dosing and efficacy, e.g., pharmacokinetics (PK), helps one identify and understand these interdependences. However, efficacy still tends to be a complicated function of PK parameters, and indeed these parameters are becoming more complex as a function of dosing regimen, viz., studies involving immunosuppressants, biotechnology drugs, sophisticated delivery systems, and dosing strategies. Stationary and time-dependent neural nets can help one identify and model such unknown complex dynamical functions with few assumptions and limited data (1-7). Neural nets can relate dosing directly to efficacy, dosing to PK, PK to efficacy, or any component in the complex associations among treatments, pharmacodynamics, efficacy, and side effects. Neural nets can also assist one in the design of clinical trials involving complex and sophisticated procedures, e.g., randomized controlled clinical trials.