The impact of omalizumab on paid and unpaid work productivity among severe Japanese cedar pollinosis (JCP) patients.

AIMS: Japanese cedar pollinosis (JCP) is a form of seasonal allergic rhinitis that affects 38.8% of the Japanese population. Particularly severe and most severe symptoms among JCP patients can lead to impairments of paid work productivity and unpaid work activities. Indeed, the current standard of care (SoC) is not always able to relieve these symptoms. Omalizumab, a novel JCP treatment recently approved in Japan, provides an effective add-on therapy to the SoC. This study estimates the effect of omalizumab on paid and unpaid work activities (i.e. its social impact) in patients with severe and most severe JCP symptoms in Japan. METHODS: The impact of omalizumab was estimated through a one-year static cohort model using the Work Productivity and Activity Impairment Allergy Specific (WPAI-AS) questionnaire derived from a clinical trial on omalizumab enrolling patients with severe and most severe JCP symptoms, which had been conducted in Japan. This effect was quantified using Japanese official statistics on employment and time use. The human capital approach and the proxy good approach were employed to monetize paid and unpaid work activities, respectively. A sensitivity analysis was implemented to account for modeling structural uncertainties. RESULTS: Our results show that the use of omalizumab might reduce the paid and unpaid work productivity losses due to severe and most severe JCP by nearly one-third. In the severe symptom period of three weeks, 36.6 million hours of lost paid and unpaid work hours could be avoided, which sums up to a monetized productivity loss of 728.3 million USD. CONCLUSIONS: Omalizumab could provide substantial benefits in terms of paid and unpaid work activities in patients with severe and most severe JCP. Our results also highlight the importance of considering unpaid work in estimating productivity costs due to poor health.

High risk human papillomavirus genotyping in clinical samples: evaluation of different commercial tests.

The aim of the present study is to compare the performance of several commercial human papillomavirus (HPV) tests in a cohort of 281 women. The hybrid capture II, the PreTect-HPV-Proofer, the linear array, and DR.HPVTMIVD were utilized to detect and type HPV in parallel with in-house PCR tests followed by direct automated sequencing or by sub-cloning and sequencing. The concordance levels along with other tests were evaluated with a Cohen's K value varying between 0.60 to 0.88, indicating good correlation with nearly perfect agreement between hybrid capture II, (HCII) and the linear array test. High sensitivity was recorded by the linear array and HCII with 100% (95% CI, 0.8021 to 1.0000) detection of cervical intraepithelial neoplasia (CIN) III by both methods. Conversely, the PreTect-HPV-Proofer showed high specificity with 12% (95% CI, 0.7966 to 0.9163) positivity on normal samples. The genotyping analysis showed that agreement among tests was only low to moderate with great differences between different HPV types. Multiple infections were detected with poor concordance and sub-cloning assays revealed the presence of a lower number of HPV in comparison to the other methods. In summary, the use of different HPV tests applied to the same group of cervical smears may possibly lead to incongruent results, suggesting the need to standardize type-specific sensitivity of genotyping methods and the need to evaluate their accuracy in detecting multiple HPV infections. This would be a prerequisite for the use of genotyping assays in cervical cancer screening programs.

Predictors of human papilloma virus (HPV) infection in Italian women.

HPV infection is a "necessary cause" of cervical cancer and it is sexually transmitted. Due to upcoming mass vaccination investigation on risk factors for infection is the basis to implement prophylactic strategy even in older women. The aim of the study was to evaluate predictors of high-risk (HR) HPV infection in adult women. Between 2006 and 2008, 100 women aged >18 years, with no previous treatment for cervical lesions, were screened for HR HPV infection in Rome, Italy. Risk factors for HPV infection were investigated through a questionnaire including: ethnicity, religion, education, marital status, sexual behavior, gynecological and obstetrical history, smoking and alcohol intake. Multivariate analysis identified the "never married-separated/divorced" status (OR: 3.38; 95% CI: 1.14-10.12) as predictor of HPV infection, while having a higher age at the first sexual intercourse (FSI) shows a protective effect (OR: 0.84; 95% CI: 0.71-1.00). A trend for the association between the infection and having more than three lifetime partners was also observed (OR: 2.57; 95% CI: 0.86-7.71). No significant association was found for other demographic characteristics investigated. These findings provide a contribution in the knowledge of an adult population defining a "high-risk" sexual behavioral profile and could be helpful to target prophylactic strategies in older woman.

Short communication: Detection of human Torque teno virus in the milk of water buffaloes (Bubalus bubalis).

Forty-four raw milk and 15 serum samples from 44 healthy water buffaloes reared in Caserta, southern Italy, the most important region in Europe for buffalo breeding, were examined to evaluate the presence of Torque teno viruses (TTV) using molecular tools. Furthermore, 8 pooled pasteurized milk samples (from dairy factories having excellent sanitary conditions) and 6 Mozzarella cheese samples were also tested. Four of the cheese samples were commercial Mozzarella cheese; the remaining 2 were prepared with TTV-containing milk. Human TTV were detected and confirmed by sequencing in 7 samples of milk (approximately 16%). No TTV were found in serum, pooled pasteurized milk, or Mozzarella cheese samples. The samples of Mozzarella cheese prepared with TTV-containing milk did not show any presence of TTV, which provides evidence that standard methodological procedures to prepare Mozzarella cheese seem to affect viral structure, making this food fit for human consumption. The 7 TTV species from water buffaloes were identified as genotypes corresponding to the tth31 (3 cases), sle 1981, sle 2031, and NLC030 (2 cases each) human isolates. Although cross-species infection may occur, detection of TTV DNA in milk but not in serum led us to believe that its presence could be due to human contamination rather than a true infection. Finally, the mode of transmission of TTV has not been determined. Contaminated of the food chain with TTV may be a potential risk for human health, representing one of the multiple routes of infection.

Targeting immune response with therapeutic vaccines in premalignant lesions and cervical cancer: hope or reality from clinical studies.

Human papillomavirus (HPV) is widely known as a cause of cervical cancer (CC) and cervical intraepithelial neoplasia (CIN). HPVs related to cancer express two main oncogenes, i.e. E6 and E7, considered as tumorigenic genes; their integration into the host genome results in the abnormal regulation of cell cycle control. Due to their peculiarities, these oncogenes represent an excellent target for cancer immunotherapy. In this work the authors highlight the potential use of therapeutic vaccines as safe and effective pharmacological tools in cervical disease, focusing on vaccines that have reached the clinical trial phase. Many therapeutic HPV vaccines have been tested in clinical trials with promising results. Adoptive T-cell therapy showed clinical activity in a phase II trial involving advanced CC patients. A phase II randomized trial showed clinical activity of a nucleic acid-based vaccine in HPV16 or HPV18 positive CIN. Several trials involving peptide-protein-based vaccines and live-vector based vaccines demonstrated that these approaches are effective in CIN as well as in advanced CC patients. HPV therapeutic vaccines must be regarded as a therapeutic option in cervical disease. The synergic combination of HPV therapeutic vaccines with radiotherapy, chemotherapy, immunomodulators or immune checkpoint inhibitors opens a new and interesting scenario in this disease.

Blood volume regulation during hemodialysis.

Hemodialysis (HD)-induced hypotension may be precipitated by severe hypovolemia. To avoid the appearance of destabilizing hypovolemias, we have developed a biofeedback control system for intradialytic blood volume (BV)-changes modeling. The system, incorporated in a dialysis machine, is based on a multivariable closed-loop control with a dependent output variable, the BV changes, and two independent control variables, the ultrafiltration rate (Qf) and dialysate conductivity (DC). The relative BV changes occurring during HD are measured by an optical device. The Qf and DC are continuously adjusted by the control model during the treatment to minimize any discrepancies between the ideal targets for the BV, the patient's body weight reductions, and the experimentally obtained results. The system manages three kinds of errors: in BV changes, the total weight loss, and the sodium balance. The latter is controlled by a dedicated kinetic model that continuously calculates the equivalent DC and, by the end of the session, tends to make the sodium balance the same as the one obtained in conventional HD with constant DC. This system's capacity to improve intradialytic hemodynamic tolerance has been assessed in a crossover study of eight highly symptomatic patients. Conventional HD (CHD; period A) was compared with blood volume-controlled dialysis sessions (BV-CHD; period B) following a protocol with an A1-B-A2 sequence, with each period lasting 1 month. A lower decrease in BV (-10.6%) was obtained during BV-CHD (period B) compared with CHD (-12.3% in period A1 and -12.5% in period A2). The predialysis to postdialysis systolic arterial pressure changes were lower in period B (-12.4%) than in period A (-20% in A1 and -17.5% in A2; P < 0.05) despite similar total Qf and mean treatment times. A significant reduction in the number of severe hypotensive episodes (three in period B v 26 in period A1 and 16 in period A2; P < 0.05) and the overall incidence of complaints, especially of muscular cramps, was found in BV-CHD. These results were reflected in a reduced need for therapeutically administered isotonic saline in each session (60 mL in B v160 mL in A1 and 95 mL in A2; P < 0.05). In conclusion, the proposed biofeedback system for intradialytic BV control may be useful to avoid severe hypovolemic states, to stabilize BV by modeling its trend, and to avoid reaching individual critical BV thresholds in hypotension-prone patients.

Epidural pressure measurement in the rat.

An original device for the epidural pressure measurement in the rat is presented. The reliability of epidural pressure as an index of intracranial pressure is discussed and several possible causes of error are examined. The device has been tested under conditions both of transient and prolonged cerebral blood volume increase, obtained by venous outflow obstruction.

Effect of natural allergen exposure on non-specific bronchial reactivity in asthmatic farmers.

The aim of the study was to assess the seasonal variability of non-specific bronchial reactivity (NSBR) evaluated with methacholine in asthmatic farmers allergic to pollens. Twenty farmers (16 male and four female) with allergy to pollens, e.g. 'Graminae' and 'Parietaria', entered the study. None of the patients had been previously treated with specific immunotherapy. Patients underwent a methacholine challenge at the first visit and then in the subsequent seasons. Four groups of tests were obtained according to the period when the challenge was performed. Group 1: challenges performed in December, January and February; group 2 in March, April and May; group 3 in June, July and August; group 4 in September, October and November. PD20 values were expressed as the natural logarithm of the cumulative dose of methacholine causing at least a 20% fall in FEV1. Bronchial hyperreactivity was highest in summer, followed by spring and autumn; in winter it was much lower. Multiple group analysis (ANOVA) showed statistically significant differences between the groups (P < 0.01). When the groups were compared individually, statistically significant differences existed only between group 1 (winter) and each of the other groups, respectively 2 (spring) (P = 0.02), 3 (summer) (P = 0.004) and 4 (autumn) (P = 0.02). The results underlined the importance of allergic inflammation in determining changes in NSBR. In the region where the study was carried out (central Italy), the grass and Paretaria pollination lasts from March to November. Therefore, farmers had a progressive increase in NSBR from spring to summer and a decrease in fall as a consequence of the varying pollen concentration in different seasons. The level of allergen exposure is, in fact, the main factor that determines the severity of bronchial inflammation, thus affecting NSBR.

Automatic control of blood volume trends during hemodialysis.

Dialysis induced hypovolemia plays an important role in triggering intradialytic hypotension. The authors developed an automatic system (BVAC) with feedback changes in the ultrafiltration rate (UFR) and dialysate conductivity (DC) to match blood volume (BV) intradialytic profiles with the desired trajectories. The system consists of three subunits: (1) an optical probe to continuously detect the BV changes derived from hemoglobin changes, and (2) a dialysis machine interfaced with (3), a personal computer in which a time-dependent model is implemented. The model is based on a dynamic regulator that can set the actual BV changes against the corresponding desired values. Any discrepancy is offset by changes in UFR and DC. To verify the efficacy of the BVAC system in reducing intradialytic cardiovascular instability, five hypotension-prone patients were studied during a three period protocol (A1-B-A2) that lasted six sessions per period per patient. During periods A1 and A2, the dialysis procedure was conventional hemodialysis (HD) with linear UFR and constant DC. During period B, both UFR and DC were automatically regulated by the BVAC system. Mean BV reduction and its variability were lower during period B than during periods A1 and A2 (-10.2%, -11.3%, and -11.5, respectively). Episodes of hypotension were significantly (P < 0.05) fewer during period B (n = 1) than during periods A1 (n = 8) and A2 (n = 5). The therapeutic interventions defined as infused milliliters of isotonic and hypertonic solution were fewer during period B compared with periods A1 and A2. Total UF and end-dialysis plasma sodium concentrations did not differ in the three study periods. BVAC was effective in improving cardiovascular tolerance to treatment.

Hemoscan: a dialysis machine-integrated blood volume monitor.

We describe an opto-electronic device capable of measuring the hemoglobin concentration (Hgb) non-invasively and continuously, hence the percentage changes in blood volume (BV) during dialysis treatment by means of the optical absorption of monochromatic light by the blood in the arterial line. This method has been validated during several in vitro and in vivo tests, during which the system has shown a low sensitivity to all the common intra-dialytic interference factors, such as oxygen saturation (max. err. = 1.6%), blood flow (max. err. = 1.8%), osmotic pressure (max. err. = 0.7%) and hydraulic pressure (max. err. = 0.6%), a high precision (std. err. < 0.1 g/dl) and a good accordance (Hgb mean err. = 0.1 g/dl; std. err. = 0.38 g/dl; BV mean err. = 0.1%; std. err. = 1.6%) with the corresponding values derived from standard laboratory tests.

Autonomic nervous function and blood volume monitoring during hemodialysis.

We studied the autonomic reflex response to hypovolemia during HD by means of spectral analysis of heart rate variability (SAHRV) in 10 hypotension prone (group A) and 10 hemodynamically stable patients (group B). UF rate normalized per total body water and blood volume fall were similar in the two groups. The sympatho-vagal balance index, calculated as the ratio between the integrals of the spectrum in the low (0.02-0.15 Hz) and in the high frequency range (0.2-0.35 Hz) rose in group B progressively from the beginning of the treatments, reaching a top at the 90th minute and remained subsequently high until the end. On the contrary this index did not show remarkable increases in group A. The differences between the two groups were statistically significant at 0 (4.6 +/- 2.9 vs 1.5 +/- 1.3), 60th (8.3 +/- 7.8 vs 2.2 +/- 2.6), 90th (17.9 +/- 13.4 vs 3.7 +/- 2.8), 150th (8.8 +/- 3.7 vs 2.7 +/- 2.8) and 210th minute (8.6 +/- 5.0 vs 2.9 +/- 2.5). In conclusion SAHRV shows an impairment of autonomic reflex response to hypovolemia in hypotension-prone patients.

Effects of automatic blood volume control over intradialytic hemodynamic stability.

Due to the crucial role of hypovolemia in the genesis of dialysis-induced hypotension, we have evaluated whether the automatic control of the intradialytic blood volume (BV) decrease along a preset trajectory might be beneficial to the hemodynamic stability during treatment. Five frequently hypotensive HD patients were studied and a 3-period-protocol (A1-B-A2) was adopted, each period lasting 6 sessions per patient. During the B periods the patient BV decrease was kept along a predefined profile, thanks to an automatic system with a retroactive control of both the ultrafiltration rate (UFR) and dialysate conductivity (DC); instead, during the A periods, conventional HD was performed, with linear UFR and constant DC, inducing a spontaneous decrease in BV. The intradialytic BV behaviour was much more stable during the B-periods (-10.2 +/- 1.4% by the end of the treatment) than during the A1 (-11.2 +/- 3%) and A2 periods (-11.5 +/- 2.5%). Only one dialysis-hypotension episode was observed during the B periods, compared to 8 and 5 during the A1 and A2 periods, respectively (p < 0.05). The automatic control of the BV changes during dialysis could improve the intra-treatment cardiovascular stability in critically-ill patients.

Model-based dialysis adequacy prediction by continuous dialysate urea monitoring.

A modeling approach for on-line estimation of urea kinetics from continuous measurement of urea concentration in the effluent dialysate stream (DUN) is presented. On-line identification of urea kinetics response parameters is used to predict and update dialysis adequacy during the treatment. Dialysis adequacy can be quantified in several ways, but its strict dependence on final urea concentration is a major fact. For this reason, a good predictive skill on the time course of DUN may enable better performances in the control of dialysis outcome by treatment parameters adjustment. A post-filter enzymatic sensor performs continuous measurement of DUN on patients undergoing standard haemodialysis. To get an early prediction of the end dialysis urea level, the solution of a variable volume double-pool (VVDP) model is used, whose parameters are identified at each time on the basis of the past DUN history Unlike the variable volume single-pool (VVSP) model, this enables a prompt and accurate estimation of the final DUN. In fact, after 75 min the estimates always differ by less than 10% from the values measured by the sensor at the end of the treatment. Moreover, values predicted by the model in the last hour always lie within 1% of measured final values. Real-time knowledge of an analytic expression for whole DUN time course also enables the accurate prediction of total removed urea, with no need of cumbersome dialysate collection techniques.

A new biosensor for continuous monitoring of the spent dialysate urea level in standard hemodialysis.

This study gives the results in terms of precision and repeatability of a new on-line urea monitoring system (Ureascan P2 Hospal) capable of measuring the urea concentrations in the spent dialysate. The Ureascan P2 Hospal (UP2H), fitted on single-pass dialysis machines (Integra-Hospal), functions by the presence of a disposable mini-reactor containing urease. The passage through the reactor of a minimum quantity of spent dialysate from the filter diluted with a pH 7 buffer solution (1 ml/min) increases its ionic strength, which is detected by a differential measurement of conductivity in proportion to the urea concentration in the dialysis liquid. We studied 13 dialysis sessions, with bicarbonate buffer, in 8 anuric patients. From 4 to 7 dialysate samples were taken during each treatment to determine the urea and 65 samples were analysed overall. Urea values from the UP2H were compared with those measured on the Dimension Du Pont analyser. Simple linear regression analysis showed an excellent correlation between the 2 measuring methods (r=0.987; p<0.001). The Bland-Altman test gave an average difference between the urea values measured with the UP2H and in the laboratory of 1.3+/-1.2 mg/dl. The agreement limits between 2 SD were -1.2 mg/dl and +3.8 mg/dl respectively. In conclusion, the UP2H we have developed has proved to be a reliable and very useful instrument for adapting, through the urea kinetic mathematical models, the dialysis dose for individual patients.

[Methods for the sampling and tracing of caprolactam monomer dispersed in the air]. / Metodi per il campionamento e la determinazione di tracce di caprolattame monomero disperso nell'aria.

The problem of hygiene in the production of epsilon-caprolactam is very important; pollution of work room air is possible when the substance is stored, transported or packed in bags. In this work toxic and irritant properties of epsilon-caprolactam are described. Infrared spectroscopic, gas chromatrographic and spectrophotometric methods used by us, for the determination of epsilon-caprolactam traces, are also described.

Biofeedback systems architecture.

The capability for a dialysis machine to use a measurement of the patient's status to automatically tune the dialysis session on-line is commonly addressed by physicians and bioengineers working in the hemodialysis field as "biofeedback." This paper presents the basics of mathematical modeling and control theory normally used in bioengineering, together with some advanced techniques, such as adaptive and multi-input/multi-output control systems. The architectural requirements for implementing biofeedback techniques in renal replacement therapy are then discussed, with due attention paid to the safety aspects, which play a central role in machines hosting such new techniques as well as their therapeutic mission. Finally, the blood volume tracking system, which is aimed at performing the intradialytic water removal, while maintaining a balance inside the body fluids compartments and thus preserving cardiovascular stability, is used as a paradigmatic example of such a class of advanced techniques. The significant results shown by the blood-volume-controlled treatments during a multicenter study focused on its clinical application (30% reduction of intradialysis collapses, 13% reduction of interdialysis symptoms) indicate the technical feasibility and the remarkable benefits of such systems, which get closer to a structurally complete artificial kidney.