Three-dimensional histology vs. serial section histology in the treatment of primary basal cell carcinoma: a randomized, prospective, blinded study of 569 tumours.

BACKGROUND: For basal cell carcinoma (BCC), only few controlled data have been published so far, which directly compare micrographically controlled surgery with conventional serial section histology. In addition to Mohs surgery, which uses cryostat sections, also three-dimensional histology (3D-histology), based on paraffin sections, is available to ensure complete control of the margins and basic sections. OBJECTIVES: To investigate the rate of local recurrence (LR) as well as the number of required re-excisions for basal cell carcinomas with serial section histology vs. 3D-histology. METHODS: We compared serial sections histology with 3D-histology in a prospective, randomized, controlled blinded trial and analysed 569 BCC of all subtypes up to 30 mm diameter, 287 BCC in the 3D group and 282 BCC in the serial section group. Excisions were performed with adapted primary resection margin according to location and size of the tumour. Surgeons were blinded at the time of surgery as they did not know which histological method will be used. Both methods used paraffin sections. RESULTS: Both groups did not differ regarding patients age, tumour location, tumour diameter, tumour subtypes or primary resection margins. In the serial section group, re-excisions were required in 21%; 24 tumours (8.4%) recurred after a median of 2.2 years. In the 3D-histology group, re-excisions were required in 39%; 10 tumours recurred (3.5%) after a median of 2.8 years. The recurrence rates differed significantly between both groups. Mean follow-up was 4.5 years. CONCLUSIONS: 3D-histology is a useful technique to detect tumour outgrowths at the excision margins, but required a high rate of re-excisions. 3D-histology was associated with a significantly lower LR rate than serial section histology.

Transmission of SARS-CoV-2 in children aged 0 to 19 years in childcare facilities and schools after their reopening in May 2020, Baden-Württemberg, Germany.

We investigated data from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected 0-19 year olds, who attended schools/childcare facilities, to assess their role in SARS-CoV-2 transmission after these establishments' reopening in May 2020 in Baden-Württemberg, Germany. Child-to-child transmission in schools/childcare facilities appeared very uncommon. We anticipate that, with face mask use and frequent ventilation of rooms, transmission rates in schools/childcare facilities would remain low in the next term, even if classes' group sizes were increased.

Assessment of Public Health and Economic Impact of Intranasal Live-Attenuated Influenza Vaccination of Children in France Using a Dynamic Transmission Model.

OBJECTIVES: We estimated the epidemiological and economic impact of extending the French influenza vaccination programme from at-risk/elderly (≥65 years) only to healthy children (2-17 years). METHODS: A deterministic, age-structured, dynamic transmission model was used to simulate the transmission of influenza in the French population, using the current vaccination coverage with trivalent inactivated vaccine (TIV) in at-risk/elderly individuals (current strategy) or gradually extending the vaccination to healthy children (aged 2-17 years) with intranasal, quadrivalent live-attenuated influenza vaccine (QLAIV) from current uptake up to 50% (evaluated strategy). Epidemiological, medical resource use and cost data were taken from international literature and country-specific information. The model was calibrated to the observed numbers of influenza-like illness visits/year. The 10-year number of symptomatic cases of confirmed influenza and direct medical costs ('all-payer') were calculated for the 0-17- (direct and indirect effects) and ≥18-year-old (indirect effect). The incremental cost-effectiveness ratio (ICER) was calculated for the total population, using a 4% discount rate/year. RESULTS: Assuming 2.3 million visits/year and 1960 deaths/year, the model calibration yielded an all-year average basic reproduction number (R 0) of 1.27. In the population aged 0-17 years, QLAIV prevented 865,000 influenza cases/year (58.4%), preventing 10-year direct medical expenses of €374 million. In those aged ≥18 years with unchanged TIV coverage, 1.2 million cases/year were averted (27.6%) via indirect effects (additionally prevented expenses, €457 million). On average, 613 influenza-related deaths were averted annually overall. The ICER was €18,001/life-year gained. The evaluated strategy had a 98% probability of being cost-effective at a €31,000/life-year gained threshold. CONCLUSIONS: The model demonstrated strong direct and indirect benefits of protecting healthy children against influenza with QLAIV on public health and economic outcomes in France.

Basal serum tryptase as risk assessment for severe Hymenoptera sting reactions in elderly.

BACKGROUND: Epidemiologic studies suggest that elderly people are more prone to develop severe anaphylactic reactions. However, the exact cause for this phenomenon remains unclear. AIMS OF THE STUDY: To study the role of the serum tryptase as a diagnostic parameter for individual risk evaluation and its impact on the severity of allergic reactions in elderly people. METHODS: Two hundred and seventy-four consecutive patients visiting the Department of Dermatology, Tübingen, Germany, who were diagnosed with honeybee or wasp venom allergy, were included in the study. RESULTS: Sting reaction severity increased with increased age and tryptase levels (P = 0.001 and P = 0.0003, respectively). Furthermore, we find not only a general increment in tryptase levels in elderly people (P = 0.0001) but also a continuous increase in tryptase concentrations even below the cut-off (11.4 microg/l) with increasing age (P = 0.0026). CONCLUSIONS: Our data confirm serum tryptase as a risk factor for severe anaphylactic reaction to hymenoptera stings. Furthermore, we give first evidence that basal serum tryptase levels increase continuously with age and being an indicator for either increased mast cell load or reactivity this can at least partly be responsible for the observed aggravated allergic reactions in elderly people. As those patients are at increased risk for life-threatening anaphylactic reactions, it should be considered to adjust VIT especially in elderly patients with elevated tryptase levels as recommended for patients with mastocytosis by increasing venom doses during VIT and by considering its life-long continuation.

Safety and efficacy of etanercept in children with juvenile idiopathic arthritis below the age of 4 years.

Little is known about the safety and efficacy of etanercept in children below the age of 4 years. Twenty-five patients with juvenile idiopathic arthritis (JIA) below the age of 4 years, who received etanercept, were documented in the German JIA Etanercept Registry. Patients with the nonsystemic JIA disease-subtype responded more frequently to treatment with etanercept than systemic onset patients. At last observation, two (20%) of the nonsystemic patients did not reach a PedACR 30 response, while six (40%) of the systemic onset patients did not respond to the therapy. Complete resolution of symptoms was observed in two (20%) nonsystemic and in five (33%) systemic onset patients with JIA. Tolerability was good with only two infections occurring in the total patients group. Patients with JIA below the age of 4 years, with a methotrexate-resistant disease course, would also benefit from treatment with etanercept, showing a good tolerability. The restriction to children older than 4 years appears to be artificial without any good rationale.

Diagnostic value of nodule palpation in onchocerciasis.

Nodule palpation is the major diagnostic tool for determining the prevalence of infection in areas of the African Programme for Onchocerciasis Control (APOC) and is recommended for identifying communities at risk and selecting them for mass drug administration. The diagnostic value of palpation, however, has not been quantified in terms of sensitivity and predictive values. We derive these measures from the probability that a nodule is palpable, which has been estimated by stochastic simulations from an extensive pre-control database. We show that nodule palpation is only reliable in highly endemic areas and that false-positive diagnoses can lead to considerable misclassifications of regions where endemicity is actually low. Its diagnostic precision is poor because of large intra- and inter-individual variability. The findings underline the need for further development of available diagnostics that allow long-term monitoring when endemicity declines.

The impact of contact structure on infectious disease control: influenza and antiviral agents.

Planning adequate public health responses against emerging infectious diseases requires predictive tools to evaluate the impact of candidate intervention strategies. With current interest in pandemic influenza very high, modelling approaches have suggested antiviral treatment combined with targeted prophylaxis as an effective first-line intervention against an emerging influenza pandemic. To investigate how the effectiveness of such interventions depends on contact structure, we simulate the effects in networks with variable degree distributions. The infection attack rate can increase if the number of contacts per person is heterogeneous, implying the existence of high-degree individuals who are potential super-spreaders. The effectiveness of a socially targeted intervention suffers from heterogeneous contact patterns and depends on whether infection is predominantly transmitted to close or casual contacts. Our findings imply that the various contact networks' degree distributions as well as the allocation of contagiousness between close and casual contacts should be examined to identify appropriate strategies of disease control measures.

Infectiousness of smallpox relative to disease age: estimates based on transmission network and incubation period.

This study investigated the infectiousness of smallpox relative to the onset of fever using a likelihood-based estimation procedure based on the observed transmission network (n=223) and on the distribution of the incubation period (n=379). Who-infected-whom information enabled us to back-calculate the infectiousness by disease age, employing a step function model for infectiousness. Frequency of secondary transmissions was highest between 3 and 6 days after onset of fever, yielding an expected daily frequency of 20.6% (95% CI 15.1-26.4) of the total number of secondary transmissions, which is consistent with previous observations. The estimated cumulative frequency suggests that 91.1% of secondary transmissions occurred up to 9 days after onset of fever. The proposed method appeared to be useful for diseases with an acute course of illness, where transmission was not hampered by depletion of susceptible contacts.

Estimation of the duration of vaccine-induced residual protection against severe and fatal smallpox based on secondary vaccination failure.

BACKGROUND: Understanding the loss of vaccine-induced immunity against smallpox is essential in determining the fraction of those who are still protected in the present population and in constructing effective countermeasures against bioterrorist attacks. METHOD: Three small Australian outbreaks from the 1880s to early 1900s were investigated. Each documented individual age at infection. The case records for Launceston, 1903, further documented the age at vaccination and disease severity, enabling estimates of the duration of protection against severe and fatal smallpox. RESULTS: A significant association between vaccination and death was observed in the outbreak in Sydney, 1881 (odds ratio of death among vaccinated individuals = 0.3; 95% confidence interval (CI): 0.1, 0.8; p = 0.02), where the time since last vaccination was similar for all vaccinated cases. In Launceston, 1903, where the age at vaccination varied widely, the median duration of partial protection against severe and fatal smallpox was estimated to be 31.7 (95% CI: 13.2, 116.2) and 53.9 (95% CI: 25.6, 123.5) years after vaccination, respectively. Whereas those in their 20s are expected to have the highest frequency of vulnerability to smallpox death in the present population, infections among those in their 30s or 40s are expected to be much less fatal. CONCLUSION: Long lasting partial protection was suggested from the outbreak records, the estimated durations of which were roughly consistent with those reported previously. In the event of a bioterrorist attack, those involved in emergency tasks before emergency vaccination practices are re-established should ideally be previously vaccinated individuals in their 30s or 40s.

High infection rates at low transmission potentials in West African onchocerciasis.

Onchocerciasis has been successfully controlled for many years in endemic countries but more than 120 million people are still at risk. Factors which stabilise the persistence of the parasite in the population must be studied to minimise the future risk of re-infection. Among these factors, the relationship between the annual transmission potential and the parasite establishment rate is a main determinant which has to date not been quantified. Using entomological information and palpation data collected by the Onchocerciasis Control Programme in West Africa prior to the initiation of control activities, we derive annual transmission potential-dependent estimates of the parasite establishment rate from statistical analyses and computer simulations. Even at very low transmission intensities, the filarial parasite Onchocerca volvulus can efficiently establish in the human population, originating from an infection process which is strongly limited with respect to the annual transmission potential. Implementing the estimates into a simplified transmission model predicts that the critical annual biting rate, below which transmission is not possible, is much lower than previously assumed. We conclude that under the current strategy of mass distribution of microfilaricides without additional measures of vector control, the risk of re-infection is higher than previously assumed.

Reinnervation-induced alterations in rat skeletal muscle.

Denervation-induced myofiber atrophy can be reversed by reinnervation. Growing reinnervated myofibers upregulate numerous molecules, many of which determine the muscle fiber type. In the present study we aimed at identifying factors that might contribute specifically to myofiber growth after reinnervation. The common peroneal nerve of 15 male Wistar rats was cut and resutured without delay (9 animals) or with a delay of 4 weeks (6 animals). We studied the transcriptional repertoire of intact reinnervated tibialis anterior muscle by microarray gene analysis. We assessed SC activation by immunolabeling using anti-MyoD and -myogenin antibodies. The percentage of SC expressing MyoD reached up to 50% of M-cadherin+ cells whereas the percentage of SC expressing myogenin was normal (<10%) in all muscles examined. The values of ipsi- and contralateral muscles did not differ significantly from one another between right and left leg (p<0.05). Thirteen known genes were differentially regulated after reinnervation compared with contralateral muscles. Five of them determine the slow-twitch fiber type (four and a half LIM domains 3, cardiac beta-myosin heavy chain, calsequestrin 2, troponin C (slow), and heart myosin light chain), and three of them are neurally regulated (thrombospondin 4, transferrin receptor, cardiac ankyrin repeat protein). The results strengthen the notion that reinnervaton affects the molecular repertoire of the myofibers directly, leading to fiber type transformation and partial reversal of the denervation phenotype. By contrast, SC do not appear to be affected by reinnervation directly. They can be activated both in reinnervated and contralateral muscles, and they do not fully differentiate. This makes them unlikely to contribute to myofiber growth.

Lipopolysaccharide-binding protein in noninfected neonates and those with suspected early-onset bacterial infection.

OBJECTIVES: To investigate postnatal lipopolysaccharide-binding protein (LBP) kinetics in term neonates and to test its diagnostic accuracy for early-onset bacterial infection (EOBI). STUDY DESIGN: A total of 99 neonates with clinical and serological signs of EOBI comprised the study group; 198 neonates with risk factors, but without EOBI, served as controls. LBP, C-reactive protein (CRP) and interleukin-8 (IL-8) were determined. RESULTS: LBP in the noninfected group increased until 24 h after birth (P < 0.05 vs 6 h). LBP and CRP correlated strongly in neonates with suspected EOBI (r = 0.63). Although LBP reached a higher sensitivity than CRP 6 and 12 h after clinical suspicion (45 (24-68) and 79% (54-94) vs 9 (0-24) and 39% (17-64); P < 0.05)), EOBI was most reliably detected by IL-8. CONCLUSION: LBP kinetics were age-dependent. LBP was not sufficiently sensitive in the prediction of EOBI.

Modelling transmission, immunity and disease of Haemophilus influenzae type b in a structured population.

An individual-based stochastic simulation model was constructed to study the epidemiology of Haemophilus influenzae type b (Hib) transmission, immunity and invasive disease. Embedded in a demographic model, the transmission model of Hib carriage employs the most important social mixing patterns with three types of contact sites (family, day-care group, and school class). The model includes immunity against invasive Hib disease, initiated and boosted by Hib carriage and cross-reactive bacterial encounters. The model reproduces the observed age patterns in Hib carriage and disease in Finland before large-scale use of the Hib conjugate vaccines. The model was used to investigate characteristics of Hib transmission. The analysis emphasizes transmission between children and adults in families while pointing out the importance of pre-school and school-aged children in maintaining Hib circulation. Carriage in these age groups is thus identified as being essential to target for sustained effects of interventions by vaccination.

The relationships between the burden of adult parasites, host age and the microfilarial density in human onchocerciasis.

We investigate the relationship between the microfilarial density in the skin and the burden of adult female Onchocerca volvulus by analysing pre-control nodulectomy data which allow for a direct approach, independent of exposure. The data of 169 patients in Burkina Faso and 182 patients in Liberia represent savannah and forest onchocerciasis in West Africa, respectively. Whereas in Burkina Faso, a saturating relationship between microfilarial density and worm burden suggests the operation of density-dependent processes within human hosts, the Liberian data show a linear relationship implying no density dependence. The differences may derive from differences between both parasite strains, i.e. the savannah or the forest strain of O. volvulus. Consistently for both parasite strains and independent of the worm burden, the microfilarial density increases with host age emphasising the concept of the acquisition of immunological tolerance. In male hosts in Liberia, the microfilarial density increases stronger with the worm burden than in female hosts, whereas such sex-specific differences cannot be found in Burkina Faso. In the methodological part of this investigation, we suggest the beta-distribution to be most appropriate for describing variability in microfilarial densities and we present an approach to consider the uncertainty in the adult parasite burden which cannot be determined precisely in helminth infections. Implications of density dependence are discussed with respect to immunological processes in the human host and with respect to the success of control programs. The relationships described show that regulatory processes between the parasite and the human host are multi-dimensional, operating within a high degree of biological variability.

The influence of competition and vaccination on the coexistence of two pneumococcal serotypes.

Streptococcus pneumoniae (pneumococcus) is one of the most important bacterial pathogens and a leading cause of mucosal infections (e.g. otitis media) and various forms of serious diseases (e.g. pneumonia, meningitis, bacteraemia) in developing and developed countries. Based on the polysaccharide capsule, there are at least 90 different pneumococcal serotypes, which may compete with each other to colonize the nasopharynx. Newly developed protein-polysaccharide conjugated vaccines have been shown to provide protection against disease caused by the serotypes included in the vaccine, and also against colonization (carriage). It is feared that yet uncommon, but nonetheless pathogenic serotypes which have been suppressed by competition, may become more prevalent in carriage and disease after large-scale use of conjugate vaccines. In this paper, we use transmission models of pneumococcal carriage to study how competition and vaccination influence the coexistence of two serotypes. According to our results, direct (physical) competition between two pneumococcal serotypes only influences colonization if the duration of naturally acquired immunity is short. By contrast, indirect (antibody-mediated) competition is of influence only if naturally acquired immunity is long lasting. Vaccination reduces the prevalence of the target serotype--an effect that is enforced by the presence of directly competing bacteria. The emergence of a non-target serotype after vaccination is only observed if bacteria compete directly. These results emphasize the importance of studying whether bacteria compete directly or indirectly and for how long people are protected in order to assess the long-term effects of sero-competition.

Density-dependent parasite establishment suggests infection-associated immunosuppression as an important mechanism for parasite density regulation in onchocerciasis.

The modulation of human immune response by filarial parasites has yielded contradictory experimental findings and attracted much controversy. We address the unresolved question of acquisition, establishment and accumulation of Onchocerca volvulus by using a modelling approach that relates computer simulations to cross-sectional data concerning parasite burdens in 913 West African onchocerciasis patients. It is shown that the acquisition of O. volvulus is not constant with host age; instead, the analysis of age profiles of parasite burdens strongly indicate the operation of immunosuppressive processes within the human host, associated with the presence of adult parasites or microfilariae. It is suggested that these processes suppress immunity against incoming infective larvae (L3), which themselves act as an immune modulating component once they have successfully overcome the barrier of concomitant immunity. Suppression of parasite-specific immunity leads to parasite establishment rates which increase along with the parasite burden, but which hardly depend on hyperendemic annual transmission potentials. Children, still immunocompetent due to low parasite burdens, acquire 0.1-0.5 adult female parasites per year, whereas older people, immunosuppressed due to high burdens, acquire 2-4 adult female parasites per year. Differences in parasite establishment between the forest and the savannah strains of O. volvulus are quantified and dynamic aspects of density-dependent parasite establishment discussed.

The influence of Emla cream on cutaneous microcirculation.

Emla cream is frequently used in surgical dermatology and in anesthesiology, for instance, during vascular surgery procedures. Because local anesthetics can have a vasoactive effect in addition to producing analgesia, we decided to document the effect of 5% Emla cream on cutaneous circulation in a prospective, placebo-controlled study. Skin circulation was monitored continuously under standardized conditions using video capillaroscopy, laser Doppler flowmetry and skin temperature. Recordings were made at the nailfold of the fourth finger (DIV) of the left hand of 12 volunteers with healthy veins over an observation period of 60 minutes under either Emla occlusive dressing or an occlusive dressing with placebo. Mean capillary red blood cell velocity changed only minimally under the Emla occlusive dressing, while placebo occlusive dressing led to a reduction of mean capillary red blood cell velocity from 0.21 mm/s to 0.12 mm/s (p<0.01). There was no statistically significant change of arterial capillary diameter under Emla or placebo occlusive dressing. Skin temperature dropped after 60 minutes of Emla cream occlusive dressing from an initial 26.7 to 24.0 degrees C (-10.1%; p<0.02). The same duration of placebo caused skin temperature to drop from 27.6 to 23.0 degrees C (-16.7%; p<0.001). Laser Doppler flux (543 nm) rose 13% with Emla (p=0.9) and dropped 41.9% under placebo occlusive dressing (p<0.03). Emla cream upregulated nutritive perfusion. No clinically relevant vasoconstrictive effects are expected from an application period of 60 minutes.

On the interpretation of age-intensity profiles and dispersion patterns in parasitological surveys.

The present paper describes how age-intensity profiles of macroparasite burdens are affected by processes underlying the distribution of the parasite numbers in host populations. In a comparative way, we consider the following 6 processes: (i) age-dependent exposure, (ii) parasite-induced host mortality, (iii) heterogeneity within, the host population, (iv) clumped infection, (v) density-dependent parasite mortality and (vi) density-dependent parasite establishment. For each of these processes, we show typical patterns in the age-intensity profile and provide, if possible, explicit and simple solutions for the age-dependent mean parasite burden and the corresponding dispersion patterns. Emphasis is given to density-dependent parasite establishment and to age-intensity profiles resulting from the superposition of different processes. By means of 2 examples we show that the interpretation of observed patterns can be ambiguous if more than 1 process takes place. These findings underline that age-intensity profiles should be interpreted on the basis of available a priori knowledge about the processes assumed to be involved. For purposes of testing different hypotheses, a simulation program is provided with which discrepancies between model prediction and data can be explored.

Endothelial accumulation of hydroxyethyl starch and functional consequences on leukocyte-endothelial interactions.

To date, accumulation of hydroxyethyl starch (HES) has been studied mainly in skin specimens, but there are no detailed reports available regarding starch accumulation in the endothelium. Because endothelial cells play an essential role during shock, we studied the accumulation of HES in human umbilical venous endothelial cells (HUVEC). HUVEC (n = 9) were incubated with a fluorescein-conjugated HES 200/0.5 (FITC-HES) at 0.5-20 mg/ml for 1-72 h. FITC-HES was internalized dose- and time-dependently by pinocytosis into secondary lysosomes. Asymptotic elimination curves showed that 50% of the formerly ingested molecules could not be eliminated. Despite accumulation, starch molecules did not attenuate the expression of E-selectin, ICAM-1 or VCAM-1 on TNF-alpha-activated HUVEC. However, apart from adhesion molecule expression, perfusion studies showed that HES reduced neutrophil adhesion by direct inhibition of integrin-mediated interactions.