Estimating 1a0 and 4a1 in a Life Table: A Model Approach Based on Newly Collected Data.

The average age of infant deaths, a10, and the average number of years lived-in the age interval-by those dying between ages 1 and 5, a41, are important quantities allowing the construction of any life table including these ages. In many applications, the direct calculation of these parameters is not possible, so they are estimated using the infant mortality rate-or the death rate from 0 to 1-as a predictor. Existing methods are general approximations that do not consider the full variability in the age patterns of mortality below the age of 5. However, at the same level of mortality, under-five deaths can be more or less concentrated during the first weeks and months of life, thus resulting in very different values of a10 and a41. This article proposes an indirect estimation of these parameters by using a recently developed model of under-five mortality and taking advantage of a new, comprehensive database by detailed age-which is used for validation. The model adapts to a variety of inputs (e.g., rates, probabilities, or the proportion of deaths by sex or for both sexes combined), providing more flexibility for the users and increasing the precision of the estimates. This fresh perspective consolidates a new method that outperforms all previous approaches.

Amantadine and/or transcranial magnetic stimulation for fatigue associated with multiple sclerosis (FETEM): study protocol for a phase 3 randomised, double-blind, cross-over, controlled clinical trial.

INTRODUCTION: Fatigue is one of the most disabling symptoms of multiple sclerosis (MS), and effective treatments are lacking. Amantadine is one of the most used treatments, although its efficacy is under debate. Transcranial magnetic stimulation (TMS) is a promising intervention that has shown positive effects in some preliminary investigations. We aim to investigate the effect of 6 weeks of amantadine and/or TMS in fatigue due to MS. METHODS AND ANALYSIS: The study is a national, multicentre, phase 3, randomised, double-blind, cross-over, placebo-controlled and sham-controlled clinical trial. Adult patients with relapsing-remitting MS, Expanded Disability Status Scale score of 1.5-4.5 and Fatigue Severity Score>4 are eligible for the trial. Participants will be randomised to one of the sequences of the study. Each sequence consists of four periods of 6 weeks of treatment and three washout periods of 12-18 weeks. All patients will receive all the combinations of therapies. The primary outcome is the Modified Fatigue Impact Scale. The secondary outcomes are the Symbol Digit Modalities Test (cognition), Beck Depression Inventory-II (depressive symptoms) and Short-Survey 12 (quality of life). Safety and cost-effectiveness will also be evaluated. An exploratory substudy including MRI and blood biomarkers will be conducted. ETHICS AND DISSEMINATION: The study is approved by the Ethics Committee of the Hospital Clinico San Carlos and the Spanish Agency of Medications and Medical Devices. All study findings will be published in scientific peer-reviewed journals and presented at relevant scientific conferences. TRIAL REGISTRATION NUMBER: EudraCT 2021-004868-95; NCT05809414.

Pregnancy-related mortality up to 1 year postpartum in sub-Saharan Africa: an analysis of verbal autopsy data from six countries.

OBJECTIVE: To compare the causes of death for women who died during pregnancy and within the first 42 days postpartum with those of women who died between >42 days and within 1 year postpartum. DESIGN: Open population cohort (Health and Demographic Surveillance Systems). SETTING: Ten Health and Demographic Surveillance Systems (HDSS) in The Gambia, Kenya, Malawi, Tanzania, Ethiopia and South Africa. POPULATION: 2114 deaths which occurred within 1 year of the end of pregnancy where a verbal autopsy interview was conducted from 2000 to 2019. METHODS: InterVA5 and InSilicoVA verbal autopsy algorithms were used to attribute the most likely underlying cause of death, which were grouped according to adapted International Classification of Diseases-Maternal Mortality categories. Multinomial regression was used to compare differences in causes of deaths within 42 days versus 43-365 days postpartum adjusting for HDSS and time period (2000-2009 and 2010-2019). MAIN OUTCOME MEASURES: Cause of death and the verbal autopsy Circumstances of Mortality Categories (COMCATs). RESULTS: Of 2114 deaths, 1212 deaths occurred within 42 days postpartum and 902 between 43 and 365 days postpartum. Compared with deaths within 42 days, deaths from HIV and TB, other infectious diseases, and non-communicable diseases constituted a significantly larger proportion of late pregnancy-related deaths beyond 42 days postpartum, and health system failures were important in the circumstances of those deaths. The contribution of HIV and TB to deaths beyond 42 days postpartum was greatest in Southern Africa. The causes of pregnancy-related mortality within and beyond 42 days postpartum did not change significantly between 2000-2009 and 2010-2019. CONCLUSIONS: Cause of death data from the extended postpartum period are critical to inform prevention. The dominance of HIV and TB, other infectious and non-communicable diseases to (late) pregnancy-related mortality highlights the need for better integration of non-obstetric care with ante-, intra- and postpartum care in high-burden settings.

Lifetime risk of maternal near miss morbidity: a novel indicator of maternal health.

BACKGROUND: The lifetime risk of maternal death quantifies the probability that a 15-year-old girl will die of a maternal cause in her reproductive lifetime. Its intuitive appeal means it is a widely used summary measure for advocacy and international comparisons of maternal health. However, relative to mortality, women are at an even higher risk of experiencing life-threatening maternal morbidity called 'maternal near miss' (MNM) events-complications so severe that women almost die. As maternal mortality continues to decline, health indicators that include information on both fatal and non-fatal maternal outcomes are required. METHODS: We propose a novel measure-the lifetime risk of MNM-to estimate the cumulative risk that a 15-year-old girl will experience a MNM in her reproductive lifetime, accounting for mortality between the ages 15 and 49 years. We apply the method to the case of Namibia (2019) using estimates of fertility and survival from the United Nations World Population Prospects along with nationally representative data on the MNM ratio. RESULTS: We estimate a lifetime risk of MNM in Namibia in 2019 of between 1 in 40 and 1 in 35 when age-disaggregated MNM data are used, and 1 in 38 when a summary estimate for ages 15-49 years is used. This compares to a lifetime risk of maternal death of 1 in 142 and yields a lifetime risk of severe maternal outcome (MNM or death) of 1 in 30. CONCLUSIONS: The lifetime risk of MNM is an urgently needed indicator of maternal morbidity because existing measures (the MNM ratio or rate) do not capture the cumulative risk over the reproductive life course, accounting for fertility and mortality levels.

Comparison of programmatic data from antenatal clinics with population-based HIV prevalence estimates in the era of universal test and treat in western Kenya.

OBJECTIVE: To compare HIV prevalence estimates from routine programme data in antenatal care (ANC) clinics in western Kenya with HIV prevalence estimates in a general population sample in the era of universal test and treat (UTT). METHODS: The study was conducted in the area covered by the Siaya Health Demographic Surveillance System (Siaya HDSS) in western Kenya and used data from ANC clinics and the general population. ANC data (n = 1,724) were collected in 2018 from 13 clinics located within the HDSS. The general population was a random sample of women of reproductive age (15-49) who reside in the Siaya HDSS and participated in an HIV sero-prevalence survey in 2018 (n = 2,019). Total and age-specific HIV prevalence estimates were produced from both datasets and demographic decomposition methods were used to quantify the contribution of the differences in age distributions and age-specific HIV prevalence to the total HIV prevalence estimates. RESULTS: Total HIV prevalence was 18.0% (95% CI 16.3-19.9%) in the ANC population compared with 18.4% (95% CI 16.8-20.2%) in the general population sample. At most ages, HIV prevalence was higher in the ANC population than in the general population. The age distribution of the ANC population was younger than that of the general population, and because HIV prevalence increases with age, this reduced the total HIV prevalence among ANC attendees relative to prevalence standardised to the general population age distribution. CONCLUSION: In the era of UTT, total HIV prevalence among ANC attendees and the general population were comparable, but age-specific HIV prevalence was higher in the ANC population in most age groups. The expansion of treatment may have led to changes in both the fertility of women living with HIV and their use of ANC services, and our results lend support to the assertion that the relationship between ANC and general population HIV prevalence estimates are highly dynamic.

Women's risk of death beyond 42 days post partum: a pooled analysis of longitudinal Health and Demographic Surveillance System data in sub-Saharan Africa.

BACKGROUND: WHO's standard definitions of pregnancy-related and maternal deaths only include deaths that occur within 42 days of delivery, termination, or abortion, with major implications for post-partum care and maternal mortality surveillance. We therefore estimated post-partum survival from childbirth up to 1 year post partum to evaluate the empirical justification for the 42-day post-partum threshold. METHODS: We used prospective, longitudinal Health and Demographic Surveillance System (HDSS) data from 30 sites across 12 sub-Saharan African countries to estimate women's risk of death from childbirth until 1 year post partum from all causes. Observations were included if the childbirth occurred from 1991 onwards in the HDSS site and maternal age was 10-54 years. We calculated person-years as the time between childbirth and next birth, outmigration, death, or the end of the first year post partum, whichever occurred first. For six post-partum risk intervals (0-1 days, 2-6 days, 7-13 days, 14-41 days, 42-122 days, and 4-11 months), we calculated the adjusted rate ratios of death relative to a baseline risk of 12-17 months post partum. FINDINGS: Between Jan 1, 1991, and Feb 24, 2020, 647 104 births occurred in the HDSS sites, contributing to 602 170 person-years of exposure time and 1967 deaths within 1 year of delivery. After adjustment for confounding, mortality was 38·82 (95% CI 33·21-45·29) times higher than baseline on days 0-1 after childbirth, 4·97 (3·94-6·21) times higher for days 2-6, 3·35 (2·64-4·20) times higher for days 7-13, and 2·06 (1·74-2·44) times higher for days 14-41. From 42 days to 4 months post partum, mortality was still 1·20 (1·03-1·39) times higher (ie, a 20% higher risk), but deaths in this interval would be excluded from measurement of pregnancy-related mortality. Extending the WHO 42-day post-partum threshold up to 4 months would increase the post-partum pregnancy-related mortality ratio by 40%. INTERPRETATION: This multicountry study has implications for measurement and clinical practice. It makes the case for WHO to extend the 42-day post-partum threshold to capture the full duration of risk of pregnancy-related deaths. There is a need for a new indicator to track late pregnancy-related deaths that occur beyond 42 days, which are otherwise excluded from global maternal health surveillance efforts. Our results also emphasise the need for international agencies to disaggregate estimates by antepartum, intrapartum, postpartum, and extended post-partum periods. Additionally, the schedule and content of postnatal care packages should reflect the extended duration of post-partum risk. FUNDING: The UK Economic and Social Research Council.

Divergent age patterns of under-5 mortality in south Asia and sub-Saharan Africa: a modelling study.

BACKGROUND: Understanding the age pattern of under-5 mortality is essential for identifying the most vulnerable ages and underlying causes of death, and for assessing why the decline in child mortality is slower in some countries and subnational areas than others. The aim of this study is to detect age patterns of under-5 mortality that are specific to low-income and middle-income countries (LMICs). METHODS: In this modelling study, we used data from 277 Demographic and Health Surveys (DHSs), 58 Health and Demographic Surveillance Systems (HDSSs), two cohort studies, and two sample-registration systems. From these sources, we collected child date of birth and date of death (or age at death) from LMICs between 1966 and 2020. We computed 22 deaths rates from each survey with the following age breakdowns: 0, 7, 14, 21, and 28 days; 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 18, and 21 months; and 2, 3, 4, and 5 years. We assessed how probabilities of dying estimated for the 22 age groups deviated from predictions generated by a vital registration model that reflects the historical mortality of 25 high-income countries. FINDINGS: We calculated mortality rates of 81 LMICs between 1966 and 2020. In contrast with the other regions of the world, we found that under-5 mortality in south Asia and sub-Saharan Africa was characterised by increased mortality at both ends of the age range (ie, younger than 28 days and older than 6 months) at a given level of mortality. Observed mortality in these regions was up to 2 times higher than predicted by the vital registration model for the younger-than-28 days age bracket, and up to 10 times higher than predicted for the older-than-6 months age bracket. This age pattern of under-5 mortality is significant in 17 countries in south Asia and sub-Saharan Africa. Excess mortality in children older than 6 months without excess mortality in children younger than 28 days was found in 38 countries. In south Asia, results were consistent across data sources. In sub-Saharan Africa, excess mortality in children younger than 28 days was found mostly in DHSs; the majority of HDSSs did not show this excess mortality. We have attributed this difference in data sources mainly to omissions of early deaths in HDSSs. INTERPRETATION: In countries with age patterns of under-5 mortality that diverge from predictions, evidence-based public health interventions should focus on the causes of excess of mortality; notably, the effect of fetal growth restriction and infectious diseases. The age pattern of under-5 mortality will be instrumental in assessing progress towards the decline of under-5 mortality and the Sustainable Development Goals. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health.

Modeling Age Patterns of Under-5 Mortality: Results From a Log-Quadratic Model Applied to High-Quality Vital Registration Data.

Information about how the risk of death varies with age within the 0-5 age range represents critical evidence for guiding health policy. This study proposes a new model for summarizing regularities about how under-5 mortality is distributed by detailed age. The model is based on a newly compiled database that contains under-5 mortality information by detailed age in countries with high-quality vital registration systems, covering a wide array of mortality levels and patterns. It uses a log-quadratic approach in predicting a full mortality schedule between ages 0 and 5 on the basis of only one or two parameters. With its larger number of age-groups, the proposed model offers greater flexibility than existing models in terms of both entry parameters and model outcomes. We present applications of this model for evaluating and correcting under-5 mortality information by detailed age in countries with problematic mortality data.

Evaluating pregnancy reporting in Siaya Health and Demographic Surveillance System through record linkage with ANC clinics.

Introduction: Health and Demographic Surveillance Systems (HDSS) are important sources of population health data in sub-Saharan Africa, but the recording of pregnancies, pregnancy outcomes, and early mortality is often incomplete. Objective: This study assessed HDSS pregnancy reporting completeness and identified predictors of unreported pregnancies that likely ended in adverse outcomes. Methods: The analysis utilized individually-linked HDSS and antenatal care (ANC) data from Siaya, Kenya for pregnancies in 2018-2020. We cross-checked ANC records with HDSS pregnancy registrations and outcomes. Pregnancies observed in the ANC that were missing reports in the HDSS despite a data collection round following the expected delivery date were identified as likely adverse outcomes, and we investigated the characteristics of such individuals. Clinical data were used to investigate the timing of HDSS pregnancy registration relative to care seeking and gestational age, and examine misclassification of miscarriages and stillbirths. Results: From an analytical sample of 2,475 pregnancies observed in the ANC registers, 46% had pregnancy registrations in the HDSS, and 89% had retrospectively reported pregnancy outcomes. 1% of registered pregnancies were missing outcomes, compared to 10% of those lacking registration. Registered pregnancies had higher rates of stillbirth and perinatal mortality than those lacking registration. In 77% of cases, women accessed ANC prior to registering the pregnancy in the HDSS. Half of reported miscarriages were misclassified stillbirths. We identified 141 unreported pregnancies that likely ended in adverse outcomes. Such cases were more common among those who visited ANC clinics during the first trimester, made fewer overall visits, were HIV-positive, and outside of formal union. Conclusions: Record linkage with ANC clinics revealed pregnancy underreporting in HDSS, resulting in biased measurement of perinatal mortality. Integrating records of ANC usage into routine data collection can augment HDSS pregnancy surveillance and improve monitoring of adverse pregnancy outcomes and early mortality.

Estimating the infant mortality rate from DHS birth histories in the presence of age heaping.

BACKGROUND: The infant mortality rate (IMR) is a critical indicator of population health, but its measurement is subject to response bias in countries without complete vital registration systems who rely instead on birth histories collected via sample surveys. One of the most salient bias is the fact that child deaths in these birth histories tend to be reported with a large amount of heaping at age 12 months. Because of this issue, analysts and international agencies do not directly use IMR estimates based on surveys such as Demographic and Health Surveys (DHS); they rely instead on mortality models such as model life tables. The use of model life tables in this context, however, is arbitrary, and the extent to which this approach appropriately addresses bias in DHS-based IMR estimates remains unclear. This hinders our ability to monitor IMR levels and trends in low-and middle-income countries. The objective of this study is to evaluate age heaping bias in DHS-based IMR estimates and propose an improved method for adjusting this bias. METHODS AND FINDINGS: Our method relies on a recently-developed log-quadratic model that can predict age-specific mortality by detailed age between 0 and 5. The model's coefficients were derived from a newly constituted database, the Under-5 Mortality Database (U5MD), that represents the mortality experience of countries with high-quality vital registration data. We applied this model to 204 DHS surveys, and compared unadjusted IMR values to IMR values adjusted with the log-quadratic model as well as with the classic model life table approach. Results show that contrary to existing knowledge, age heaping at age 12 months rarely generates a large amount of bias in IMR estimates. In most cases, the unadjusted IMR values were not deviating by more than +/- 5% from the adjusted values. The model life table approach, by contrast, introduced an unwarranted, downward bias in adjusted IMR values. We also found that two regions, Sub-Saharan Africa and South Asia, present age patterns of under-5 mortality that strongly depart from the experience represented in the U5MD. For these countries, neither the existing model life tables nor the log-quadratic model can produce empirically-supported IMR adjustments. CONCLUSIONS: Age heaping at age 12 months produces a smaller amount of bias in DHS-based IMR estimates than previously thought. If a large amount of age heaping is present in a survey, the log-quadratic model allows users to evaluate, and whenever necessary, adjust IMR estimates in a way that is more informed by the local mortality pattern than existing approaches. Future research should be devoted to understanding why Sub-Saharan African and South Asian countries have such distinct age patterns of under-five mortality.

Age patterns of under-5 mortality in sub-Saharan Africa during 1990-2018: A comparison of estimates from demographic surveillance with full birth histories and the historic record.

BACKGROUND: Estimates of under-5 mortality (U5M) for sub-Saharan African populations often rely heavily on full birth histories (FBHs) collected in surveys and model age patterns of mortality calibrated against vital statistics from other populations. Health and Demographic Surveillance Systems (HDSSs) are alternate sources of population-based data in much of sub-Saharan Africa, which are less formally utilized in estimation. OBJECTIVE: In this study we compare the age pattern of U5M in different African data sources (HDSSs, Demographic and Health Surveys (DHS), and Multiple Indicator Cluster Surveys (MICS)), and contrast these with the historical record as summarized in the Human Mortality Database and model age patterns. METHODS: We examined the relative levels of neonatal, postneonatal, infant, and child mortality across data sources. We directly compared estimates for DHS and MICS subnational regions with HDSS, and used linear regression to identify data and contextual attributes that correlated with the disparity between estimates. RESULTS: HDSS and FBH data suggests that African populations have higher levels of child mortality and lower infant mortality than the historic record. This age pattern is most explicit for Western African populations, but also characterizes data for other subregions. The comparison between HDSS and FBH data suggests that FBH estimates of child mortality are biased downward. The comparison is less conclusive for neonatal and infant mortality. CONTRIBUTION: This study questions the practice of using model age patterns derived from largely high-income settings for inferring or correcting U5M estimates for African populations. It also highlights the considerable uncertainty around the consistency of HDSS and FBH estimates of U5M.

The Behavior of the Type of Peritoneal Transport in the Inflammatory and Oxidative Status in Adults Under Peritoneal Dialysis.

Peritoneal dialysis (PD) is an alternative for managing the end-stage renal disease (ESRD). The peritoneal membrane (PM) is not just a membrane that passively responds to diffusion and convection. The characteristics of PM result in the peritoneal equilibrium test (PET) and with this test is possible to obtain the type of peritoneal transport (PT). The patient on PD can be classified in different types of PT as; Low, Low Average, High Average, and High. The aim of the study was to compare the inflammatory cytokines, oxidants, antioxidants, and oxidative DNA damage markers in the different types of PT. A cross-sectional analytical study of 77 adult PD patients was performed. Levels of lipoperoxides (LPO) were higher in all types of PT vs. healthy volunteer controls (HC) (p < 0.0001). Nitric oxide (NO) levels were found significantly down-regulated in all types of PT (p < 0.0001). The activity of the superoxide dismutase enzyme (SOD) was found to be significantly increased in all types of PT vs. the HC (p < 0.0001). The levels of the DNA repair enzyme were found to be decreased in all types of PT. The levels of the pro-inflammatory cytokines TNF-α, IL-6, the marker of oxidative DNA damage, 8-IP and the total antioxidant capacity (TAC) were all significantly decreased, contrary to the levels in HC, possibly by the clearance in the dialysis fluid in all types of PT or due to down-regulation of their expression. In conclusion, we found significant changes in markers of inflammation, oxidative stress, and oxidative damage to DNA in all types of PT; Low, low average, high average, and high PT in the values of D/P creatinine at 4 h compared to HC.

Characterization of the visco-elastic properties of hyaluronic acid.

BACKGROUND: Hyaluronic acid (HA) is a polysaccharide present in almost all animal tissues, in which it carries out important biological functions, among them, the protection of the joints by lubricating them and dampening the tension in them. OBJECTIVE: This study compares the viscoelastic properties of several commercial preparations of HA, to determine their suitability for use as viscosupplementation therapy in joint pathology (osteoarthritis). METHODS: 4 HA hydrogels: Durolane®, Synocrom_Forte_One®, Synvisc_One® and Viscoplus_Matrix® and 4 HA solutions: Ostenil®, Ostenil_Plus®, Viscoplus_Gel® and Orthovisc® were analyzed to compare their viscoelatsic rheological parameters using an oscillatory-rotational rheometer. RESULTS: With respect to the 4 HA hydrogels, comparison of crossover frequencies allowed division into two main groups: Synvisc_One® and Viscoplus_Matrix®, with crossover frequencies in the order of magnitude of 10-2 Hz, while Synocrom_Forte_One® and Durolane® showed crossover frequencies on the order of 10-1 Hz. Only one of the 4 HA solutions, Viscoplus_Gel®, showed a crossover frequency on the order of 10-2, whereas Ostenil_Plus® and Orthovisc® showed crossover frequencies on the order of 10-1, and Ostenil® remained as a predominantly viscous fluid for frequencies as high as 4.8 Hz. CONCLUSIONS: The viscoelastic properties of the HA preparations can be ordered according to the values of G∗ (the rigidity, or vector sum of the elastic modulus G' and the viscous modulus G'') at both transition points (0.5 and 2.5 Hz) as follows: Viscoplus_Matrix®  > Viscoplus_Gel®  > Durolane®  > Synocrom_Forte_One®  > Ostenil_Plus®  > Synvisc_One®  > Orthovisc®  > Ostenil®.

ABCG2/BCRP interaction with the sea grass Thalassia testudinum.

BACKGROUND: The aqueous ethanolic extract from leaves of the marine plant Thalassia testudinum has shown antioxidant, cytoprotective, and neuroprotective properties. The chemical composition of this extract, rich in polyphenols, could interfere with active transport of drugs out of the cell and circumvent the phenomenon of multidrug resistance (MDR). The extract can act as an MDR modulator through its interaction with efflux transporters. The ABCG2/BCRP has been shown to confer MDR acting in tumor cells. METHODS: To evaluate the interaction of ABCG2/BCRP with the extract, studies in cells overexpressing human BCRP transporter and its murine ortholog Bcrp1 were performed. RESULTS AND CONCLUSIONS: T. testudinum extract could be included as MDR modulator, as interaction with ABCG2/BCRP has been shown through flow cytometry and MTT assays. The cells overexpressing ABCG2/BCRP in the presence of the extract (25-150 µg/mL) decreased the survival rates of the anti-tumoral mitoxantrone. Our results support its inclusion as a possible MDR modulator against tumor cells that overexpress ABCG2/BCRP.

Long-term follow-up of dose-adjusted EPOCH plus rituximab (DA-EPOCH-R) in untreated patients with poor prognosis large B-cell lymphoma. A phase II study conducted by the Spanish PETHEMA Group.

This prospective multi-institutional phase II study was designed to assess the efficacy and safety of dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin) plus rituximab (DA-EPOCH-R) in untreated patients with poor prognosis large B-cell lymphomas. Eighty-one patients diagnosed with diffuse large B-cell lymphoma (DLBCL, n = 68), primary mediastinal DLBCL (n = 6) and follicular lymphoma Grade 3b (n = 7), with an age-adjusted International Prognostic Index >1, were eligible for analysis. Median age was 60 years (range: 21-77). Sixty-five patients (80·2%) achieved complete response. After a median follow-up time of 64 months, 10-year event-free survival and overall survival (OS) were 47·8% and 63·6%, respectively. None of the studied clinical and biological characteristics were associated with poorer outcome. Interestingly, patients with BCL6 rearrangement achieved a 10-year OS of 100%, while patients with BCL2 rearrangement exhibited a poorer outcome compared to activated B-cell tumours and germinal centre B-cell without BCL2 rearranged tumours. Results achieved with DA-EPOCH-R showed a good long-term outcome and a tolerable toxicity profile in high-risk large B cell lymphoma patients. Outcome was not affected by tumour cell proliferation or by cell of origin, highlighting the requirement of new biological markers for patient subclassification of high-risk DLBCL patients.

Structural determinants of peripheral O-arylcarbamate FAAH inhibitors render them dual substrates for Abcb1 and Abcg2 and restrict their access to the brain.

The blood-brain barrier (BBB) is the main entry route for chemicals into the mammalian central nervous system (CNS). Two transmembrane transporters of the ATP-binding cassette (ABC) family - breast cancer resistance protein (ABCG2 in humans, Abcg2 in rodents) and P-glycoprotein (ABCB1 in humans, Abcb1 in rodents) - play a key role in mediating this process. Pharmacological and genetic evidence suggests that Abcg2 prevents CNS access to a group of highly potent and selective O-arylcarbamate fatty-acid amidohydrolase (FAAH) inhibitors, which include the compound URB937 (cyclohexylcarbamic acid 3'-carbamoyl-6-hydroxybiphenyl-3-yl ester). To define structure-activity relationships of the interaction of these molecules with Abcg2, in the present study we tested various peripherally restricted and non-restricted O-arylcarbamate FAAH inhibitors for their ability to serve as transport substrates in monolayer cultures of Madin-Darby Canine Kidney-II (MDCKII) cells over-expressing Abcg2. Surprisingly, we found that the majority of compounds tested - even those able to enter the CNS in vivo - were substrates for Abcg2 in vitro. Additional experiments in MDCKII cells overexpressing ABCB1 revealed that only those compounds that were dual substrates for ABCB1 and Abcg2 in vitro were also peripherally restricted in vivo. The extent of such restriction seems to depend upon other physicochemical features of the compounds, in particular the polar surface area. Consistent with these in vitro results, we found that URB937 readily enters the brain in dual knockout mice lacking both Abcg2 and Abcb1, whereas it is either partially or completely excluded from the brain of mice lacking either transporter alone. The results suggest that Abcg2 and Abcb1 act together to restrict the access of URB937 to the CNS.