A Note on the Impact of Portfolio Overlapping in Tests of the Fama and French Three-Factor Model

In the three-factor model of Fama and French (1993), portfolio returns are explained by the factors Small Minus Big (SMB) and High Minus Low (HML) which capture returns related to firm capitalization (size) and the book-to-market ratio (B/M). In the standard approach of the model, both the test portfolios and the factor portfolios SMB and HML are formed on the basis of size and B/M. This gives rise to a potential overlapping bias in the time-series regressions. Based on a resampling method and the split sample approach already proposed by Fama and French (1993), we provide an in-depth analysis of the effect of overlapping for a broad sample of European stocks. We find that the overlapping bias is non-negligible, contrary to what seems to be general opinion. As a consequence, the standard approach of applying the three-factor model tends to overestimate the ability of the model to explain the cross-section of stock returns

Different Outcomes of Experimental Hepatitis E Virus Infection in Diverse Mouse Strains, Wistar Rats, and Rabbits

Hepatitis E virus (HEV) is the causative agent of acute hepatitis E in humans in developing countries, but autochthonous cases of zoonotic genotype 3 (HEV-3) infection also occur in industrialized countries. In contrast to swine, rats, and rabbits, natural HEV infections in mice have not yet been demonstrated. The pig represents a well-established large animal model for HEV-3 infection, but a suitable small animal model mimicking natural HEV-3 infection is currently missing. Therefore, we experimentally inoculated C57BL/6 mice (wild-type, IFNAR−/−, CD4−/−, CD8−/−) and BALB/c nude (nu/nu) mice, Wistar rats, and European rabbits with a wild boar-derived HEV-3 strain and monitored virus replication and shedding, as well as humoral immune responses. HEV RNA and anti-HEV antibodies were detected in one and two out of eight of the rats and all rabbits inoculated, respectively, but not in any of the mouse strains tested. Remarkably, immunosuppressive dexamethasone treatment of rats did not enhance their susceptibility to HEV infection. In rabbits, immunization with recombinant HEV-3 and ratHEV capsid proteins induced protection against HEV-3 challenge. In conclusion, the rabbit model for HEV-3 infection may serve as a suitable alternative to the non-human primate and swine models, and as an appropriate basis for vaccine evaluation studies

Феномен веры в мистическом опыте просветления

В статье исследуется феномен религиозной веры и делается вывод о существовании двух ее уровней. Первый из них - "вера просительная" (со многим количеством условий), характерна для человека, воспринимающего себя как смертное Тело-Эго и ориентированного на страх. Совершенной формой религиозной веры может считаться только "вера абсолютная" (безусловная), достижение которой является основной целью мистической практики просветления. Она характеризуется полным уничтожением Эго, формированием безусловного доверия и любви к Богу. Вера в имманентных мистических учениях приобретает форму доверия к своему истинному "Я"-Атману. Вера в трансцендентно-имманентной мистике приобретает форму доверия к трансцендентной силе, что подразумевает безусловную отдачу Ее воле.У статті проводиться дослідження феномену релігійної віри. Робиться висновок про існування двох її рівнів. Перший з них - "віра прохальна" (з багатьма умовами), характерна для людини, що сприймає себе як смертне Тіло-Его та зорієнтована на страх. Досконалою формою релігійної віри можна вважати тільки "віру абсолютну" (безумовну), досягнення якої постає основною метою містичної практики просвітлення. Цей рівень віри характеризується повним знищенням Его, формуванням безумовної довіри та любові до Бога. Віра у іманентних містичних ученнях має форму довіри до свого істинного "Я"-Атману. Віра в трансцендентно-іманентній містиці приймає форму довіри до трансцендентної сили, що вимагає безумовної віддачі Її волі.The phenomenon of religious faith is investigated in the article. The conclusion is that there are two levels of it. First of them is "faith-request" (with a number of conditions), it is typical for a person who perceives oneself as a mortal Body - Ego and who is orientated on fear. Just "absolute faith" (unconditional) can be considered to be a perfect form of religious faith, and the achievement of it is the main purpose of mystical practice of enlightening. It is characterized with complete destroying of Ego, with forming of unconditional trust and love to God. Faith in immanent mystical teachings acquires the form of trust to own true "I" - Atman. Faith in transcendental immanent mystics acquires the form of trust to transcendental power that means unconditional exposing to His will

Prescribing of long-acting beta-2-agonists/inhaled corticosteroids after the SMART trial

Background After the SMART trial evaluating the safety of salmeterol (long-acting beta-2-agonist (LABA)) in asthma patients, regulatory actions were taken to promote a guideline-adherent prescribing of LABA only to patients receiving inhaled corticosteroids (ICS). We aim to analyse LABA- and ICS-related prescription patterns after the SMART trial in Germany. Methods Patients documented in the Bavarian Association of Statutory Health Insurance Physicians database (approximately 10.5 million people) were included if they had a diagnosis of asthma and at least one prescription of LABA and/or ICS between 2004 and 2008. Annual period prevalence rates (PPRs) were estimated and Cochrane Armitage tests were used for time trend analyses. Results Highest annual PPRs were found for budesonide and the fixed combination of salmeterol/fluticasone. The proportion of “concomitant LABA and ICS users” increased from 52.0 to 57.6% within the study period, whereas for “LABA users without ICS” a slight decrease from 6.5 to 5.4% was found. In 2008, the proportion of patients with at least one quarter with a LABA prescription without concomitant ICS was highest in elderly, male patients (≈20%). In the majority of these patients, a concomitant diagnosis of COPD (i.e. asthma-COPD overlap syndrome [ACOS]) was present. Conclusions Between 2004 and 2008, we found a moderate increase in guideline-adherent LABA prescribing in a representative German population. Elderly men received a significant number of LABA prescriptions without concomitant ICS probably due to ACOS

Prion Infectivity and PrPBSE in the Peripheral and Central Nervous System of Cattle 8 Months Post Oral BSE Challenge

After oral exposure of cattle with classical bovine spongiform encephalopathy (C-BSE), the infectious agent ascends from the gut to the central nervous system (CNS) primarily via the autonomic nervous system. However, the timeline of this progression has thus far remained widely undetermined. Previous studies were focused on later time points after oral exposure of animals that were already 4 to 6 months old when challenged. In contrast, in this present study, we have orally inoculated 4 to 6 weeks old unweaned calves with high doses of BSE to identify any possible BSE infectivity and/or PrPBSE in peripheral nervous tissues during the first eight months postinoculation (mpi). For the detection of BSE infectivity, we used a bovine PrP transgenic mouse bioassay, while PrPBSE depositions were analyzed by immunohistochemistry (IHC) and by protein misfolding cyclic amplification (PMCA). We were able to show that as early as 8 mpi the thoracic spinal cord as well as the parasympathetic nodal ganglion of these animals contained PrPBSE and BSE infectivity. This shows that the centripetal prion spread starts early after challenge at least in this age group, which represents an essential piece of information for the risk assessments for food, feed, and pharmaceutical products produced from young calves

Do proton pump inhibitors increase the risk of dementia? A systematic review, meta‐analysis and bias analysis

AimPrevious studies on the association between proton pump inhibitor (PPI) intake and the increased risk of dementia has shown discrepancies in their conclusions. We aimed to provide updated evidence based on extensive bias assessments and quantitative sensitivity analyses. MethodsWe searched the databases PubMed, EMBASE, SCOPUS, CENTRAL and for prospective studies that examined an association between PPI use and dementia, up to February 2022. Each study was assessed using the Cochrane risk of bias assessment tools for non-randomized studies of interventions (ROBINS-I) or randomized trials (RoB2). Pooled risk ratios (RRs) and 95% prediction intervals were computed using random-effects models. Sensitivity analyses were adjusted for small-study bias. ResultsWe included nine observational studies with 204 108 dementia cases in the primary analysis on the association between PPI use vs. non-use and dementia, and the RR was 1.16 (95% CI = 1.00;1.35). After adjusting for small-study bias by Copas selection model and Rucker's shrinkage procedure, the RR was 1.16 (1.02;1.32) and 1.15 (1.13;1.17), respectively. A subgroup analysis of PPI use vs. non-use regarding Alzheimer's disease risk yielded an RR of 1.15 (0.89;1.50). The secondary analysis on the risk of dementia by use of PPI vs. histamine-2 receptor antagonist showed an RR of 1.03 (0.66;1.62). ConclusionThis meta-analysis provided no clear evidence for an association between PPI intake and the risk of dementia. Due to discrepancies in sensitivity analyses, however, some risk of dementia by PPI use cannot be ruled out. Since an unequivocal conclusion is still pending, further research is warranted

Emulating a target trial of proton pump inhibitors and dementia risk using claims data

Background and purpose Understanding the adverse effects of proton pump inhibitors (PPIs) is important due to their widespread use, but the available evidence for an increased dementia risk amongst patients taking PPIs is inconclusive. The present study aimed to estimate the causal effect of PPIs on the risk of dementia by target trial emulation and time-varying exposure modeling. Methods Using claims data of 2,698,176 insured people of a large German statutory health insurer, a target trial was conceptualized in which individuals aged 40 years and older were classified as PPI initiators or non-initiators between 2008 and 2018, and were followed until diagnosis of dementia, death, loss to follow-up or end of study. Incidence of dementia (International Classification of Diseases 10 codes F00, F01, F03, F05.1, G30, G31.0, G31.1, G31.9 and F02.8+G31.82) was defined applying a 1-year lag window. Weighted Cox models were used to estimate the effect of PPI initiation versus non-initiation on dementia risk and weighted pooled logistic regression was used to estimate the effect of time-varying use versus non-use. Results In all, 29,746 PPI initiators (4.4%) and 26,830 non-initiators (1.3%) were diagnosed with dementia. Comparing PPI initiation with no initiation, the hazard ratio for dementia was 1.54 (95% confidence interval 1.51-1.58). The hazard ratio for time-dependent PPI use versus non-use was 1.56 (95% confidence interval 1.50-1.63). Differentiated subtypes, including unspecified dementia, Alzheimer's disease and vascular dementia, showed increased risk by PPI initiation and time-varying PPI use. Conclusions This study suggests that PPI initiation and time-varying PPI use may increase overall dementia risk

Differences in treatment and monitoring of chronic myeloid leukemia with regard to age, but not sex: Results from a population-based study

There are established guidelines for treatment and monitoring of chronic myeloid leukemia (CML) but little is known about routine care. Data on ICD-10 codes as well as prescribed medications were available for 10.5~million patients in the statutory health insurance system in Bavaria for the years 2010 to 2016. Also, data on the molecular and cytogenetic monitoring were integrated. A total of 1714 adult patients with CML were observed. Only 50.8% received more than 67.5 daily doses per quarter year (target: 91.5) while 18.2% did not receive any tyrosine kinase inhibitor (TKI). The median number of daily doses was at least 80 doses per quarter year for all age groups in men, but decreased to 62 doses in elderly women. With this exception, no differences between men and women were observed. The percentage of patients without any TKI increased with age. The median number of molecular examinations was 3.54 independent of age and sex. Even in a highly developed country, still a considerable number of patients with CML seem to not receive adequate treatment, whereas molecular monitoring can be considered satisfactory

Етнологія релігії – актуальна сфера українського релігієзнавства

Background: Inhaled long-acting beta-2-adrenoceptor agonists (LABA) are frequently used in patients suffering from asthma and chronic obstructive pulmonary disease (COPD). For evaluation of real-life data, drug consumption studies are needed but results might be widely influenced due to methodological differences in particular regarding inter-country comparisons. Objectives: This study aims to compare the LABA prescribing in the general population and specifically in patients suffering from asthma and/or COPD in five European countries. Methods: Crude and age- and sex-standardized (European 2008 reference population) annual period prevalence rates per 10,000 persons were calculated for the period 2002-2009 based on seven European electronic health record databases (Denmark, Germany, Spain, the Netherlands (2), and the United Kingdom (2)). Stratification by sex, age, and indication were performed for the annual period prevalence rates. Results: In all databases, we observed an increase in LABA prescriptions during the study period for the general population and for patients suffering from asthma and/or COPD. In 2008, the highest standardized period prevalence was observed in the Dutch Mondriaan-AHC and the Spanish BIFAP database (443.3 and 395.5 per 10,000 persons), and the lowest in the German Bavarian Claims and Dutch Mondriaan- NPRCD database (278.7 and 290.6 per 10,000 persons). Prevalence rates for LABA increased with age and were highest in patients over 70 years. Patients with a combined diagnosis of asthma and COPD had higher prevalence rates of LABA compared to patients with a single diagnosis of asthma or COPD. The proportion of patients with one inhaled LABA prescription only ranged from 14% (UK databases) to 35% (Spanish BIFAP database) in 2008 in the general population. Conclusions: By using a standardized protocol, we demonstrated inter- and intra-country differences in LABA prescriptions. A general increase of LABA prescriptions during the study period was observed in all databases

Effect of Q211 and K222 PRNP polymorphic variants in the susceptibility of goats to oral infection with Goat-BSE

Background. The prion protein-encoding gene (PRNP) is one of the major determinants for scrapie occurrence in sheep and goats. However, its effect on bovine spongiform encephalopathy (BSE) transmission to goats is not clear. Methods. Goats harboring wild-type, R/Q211 or Q/K222 PRNP genotypes were orally inoculated with a goat-BSE isolate to assess their relative susceptibility to BSE infection. Goats were killed at different time points during the incubation period and after the onset of clinical signs, and their brains as well as several peripheral tissues were analyzed for the accumulation of pathological prion protein (PrPSc) and prion infectivity by mouse bioassay. Results. R/Q211 goats displayed delayed clinical signs compared with wild-type goats. Deposits of PrPSc were detected only in brain, whereas infectivity was present in peripheral tissues too. In contrast, none of the Q/K222 goats showed any evidence of clinical prion disease. No PrPSc accumulation was observed in their brains or peripheral tissues, but very low infectivity was detected in some tissues very long after inoculation (44–45 months). Conclusions. These results demonstrate that transmission of goat BSE is genotype dependent, and they highlight the pivotal protective effect of the K222 PRNP variant in the oral susceptibility of goats to BSE. <br/