Multi-center clinical trials: Randomization and ancillary statistics

The purpose of this paper is to investigate and develop methods for analysis of multi-center randomized clinical trials which only rely on the randomization process as a basis of inference. Our motivation is prompted by the fact that most current statistical procedures used in the analysis of randomized multi-center studies are model based. The randomization feature of the trials is usually ignored. An important characteristic of model based analysis is that it is straightforward to model covariates. Nevertheless, in nearly all model based analyses, the effects due to different centers and, in general, the design of the clinical trials are ignored. An alternative to a model based analysis is to have analyses guided by the design of the trial. Our development of design based methods allows the incorporation of centers as well as other features of the trial design. The methods make use of conditioning on the ancillary statistics in the sample space generated by the randomization process. We have investigated the power of the methods and have found that, in the presence of center variation, there is a significant increase in power. The methods have been extended to group sequential trials with similar increases in power.Comment: Published in at http://dx.doi.org/10.1214/07-AOAS151 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

Diabetes melitus

Dijabetes je za sada neizlječiva kronična bolest koja nastaje kao posljedica oštećenja betastanica gušterače što proizvode hormon inzulin ili kao posljedica rezistencije tkiva na inzulin. Obilježen je relativnim ili apsolutnim manjkom inzulina s posljedičnom hiperglikemijom, koja s vremenom može dovesti do oštećenja organskih sustava. Ovisno o tome je li riječ o rezistenciji (neosjetljivosti) tkiva na inzulin ili potpunom uništenju beta-stanica, razlikujemo dva tipa dijabetesa: tip 1 ili dijabetes ovisan o inzulinu i tip 2 ili dijabetes neovisan o inzulinu. Tip 1 najčešće se javlja u ranijoj životnoj dobi (oko 12 godina) dok tip dva nastaje kasnije, poslije 40. Iako se točni uzroci ove bolesti još uvijek ne znaju smatra se da za nastanak važnu ulogu igraju nasljedne osobine, loša prehrana i okoliš (npr. virusna infekcija gušterače).Diabetes is for now incurable chronic disease which appears as a result of damage of betacells which produce hormone insulin or as a result of tissue resistance to that hormone.It is marked by absolute or relative deficiency of insulin, causing hyperglycemia which can eventually lead to damage of many organic systems. Depending is it a word of tissue resistance or total destruction of beta-cells we distinguish two types: type 1 or insulin dependent and type 2 or insulin independent. Type 1 ussualy occurs in younger age while type 1occurs in the middle age (after 40). Although the precise etiology of diabetes is uncertain reasearchers believe that factors as genetics, poor diet (malnutrition) and environment (virus affecting pancreas) may be the trigger of this disease

Goodbye Buybacks? Why Recent Stock Buyback Reform Proposals Go Beyond What Is Necessary

This note provides an overview of the intensifying debate around the impact that stock buybacks have on economic inequality and the proposals designed to reform the practice. With the advent of the Securities and Exchange Commission’s (SEC) 1982 promulgation of Rule 10b-18, corporations began allocating vast portions of their profits to stock buybacks. In recent years, this practice has become increasingly more common and has surpassed previous historical benchmarks. Critics of stock buybacks primarily view the practice as a misuse of excess corporate funds that could instead be allocated to improve employee working conditions, benefits, and future outcomes. Opponent’s concerns surrounding buybacks and inequality have been fueled by recent corporate tax cuts under the Trump administration. In many instances, additional funds provided by these tax cuts have been used to conduct buybacks as workers’ wages remain stagnant and executive compensation becomes more frequently tied to stock-based instruments. As a result of stock price increases associated with buyback announcements, issues around the incentive for executives to initiate such programs have come into question. In an effort to curb buybacks, many prominent lawmakers and academics have undertaken efforts to reform current regulations governing corporations conducting repurchase programs. However, proponents of buybacks believe that concerns related to buybacks impact on economic inequality are misplaced and potentially jeopardize legitimate uses of such programs. This Note examines the arguments shaping this debate and presents a reform proposal which endeavors to provide a balanced approach to regulating buybacks by modifying existing disclosure frameworks

A Group Level of Aspiration Technique as a Measure of Personality Rigidity

The problem of personality rigidity or the persistence of maladaptive behavior is becoming increasingly important in our culture. As part of a series of studies of the Preventive Psychiatry Project of the Iowa Child Welfare Research Station concerning this variable, it was decided to develop a group level of aspiration technique which would provide an operational measure of this concept. Inherent in such a technique is the opportunity for the subject to make numerous shifts of his goal level. The capacity to change goals in the light of new experience is an integral aspect of flexibility, and conversely an inability to shift goals may be an expression of rigidity. Most level of aspiration tasks are individually administered and data collection is a slow process. Those level of aspiration situations (4) which are group administered lack criterion validity. A valid group level of aspiration technique would, therefore, offer the advantages of more rapid and more extensive sampling, without loss of the predictive value of the individual task. If this group level of aspiration technique provides a valid measure of rigidity, it is predicted that those subjects considered highly rigid in terms of this measure would tend to receive higher scores on the California Ethnocentrism Scale (1) and could also be discriminated from flexible subjects on a Short Form of the Wesley Rigidity Scale (11). Another cross validation of the group level of aspiration technique as a measure of rigidity would be a high degree of relationship with a generally accepted, standard, individual level of aspiration technique, in this case the Rotter Board. In addition, if this group form meets the criteria of an adequate level of aspiration situation, a positive correlation should exist between goal setting behavior in these two distinct tasks

Morphometric analysis of muscularis proper and myenteric plexus of the normal human oesophagus. Age related changes

Background: Oesophagus is a muscular tube that transports food and liquidsby coordinated contraction of its muscular lining led by stimuli from the nerveplexus. Its muscularis proper layer consists of muscle cells, connective tissue andmyenteric plexus. The aim of our histomorphometric study was to reveal detailedcharacteristics of this layer, cell number, volume, orientation, properties of myentericplexus as well as changes related to aging.Materials and methods: Oesophagus tissue samples from 17 male cadavers weretaken from the cranial and thoracic parts. Samples were divided in 2 groups: younger(ages 21–45) and older (ages 66–78). The tissue was routinely processed,embedded and serially sectioned. Sections were stained with Masson-Goldner andCresyl-violet dyes. Digital images were analysed with the image analysis software.Statistics were performed with SPSS software.Results: The average thickness of the cranial part of the oesophageal wall andmuscularis proper was 2590 μm and 1197 μm, respectively in the younger and2453 μm and 1144 μm in the older group. Overall volume of the muscle tissuewas slightly larger in the thoracic part, and in the younger group comparedto the cranial part and the older group. The average number of the striatedmuscle cells per 100 μm in the cranial part was 771.5 and 749.7 in the youngerand the older group, respectively. Striated cells were significantly lesspresent only in the lower thoracic part of the oesophagus. In the older group,smaller striated muscle cells dominated over the larger ones. In the youngergroup, majority of the striated muscle cells were mid-sized. The thickness ofthe circular layer of muscularis proper was more affected by aging than thelongitudinal one. Ganglion cells number was lower in the older group, butplexus area was unchanged.Conclusions: Aging affects muscularis proper and myenteric plexus of the oesophagus.Major differences can be observed in the striated muscle cells size, volumeof the circular layer and number of the ganglionic cells in the myenteric plexus

Development of Chemical Literacy Test Instruments on Electrolyte and Nonelectrolyte Solution Topic

This study aims to develop items about chemical literacy in electrolyte solution materials and nonelectrolyte solutions. This research applies research and development methods with ADDIE development model (Analysis, Design, Development, Implementation, and Evaluation). Instrument trial samples of 135 students of class XI and XII of one of the public high schools in Pasuruan Regency with the criteria of having received learning on electrolyte and nonelectrolyte solution topic. Content validation by expert validators shows an average value of 95% so it is categorized as excellent. The results of empirical validity showed the result that 25 questions were declared valid with a cronbach alpha value of 0.797 with a very high degree of consistency. Furthermore, the differentiation of all question items is stated to be very good with 3 questions categorized as difficult and 22 questions categorized as moderate.  Keywords: Assessment instruments, chemical literacy, electrolyte and nonelectrolyte solutions.DOI: http://dx.doi.org/10.23960/jppk.v11.i3.2022.07

Diabetes melitus

Dijabetes je za sada neizlječiva kronična bolest koja nastaje kao posljedica oštećenja betastanica gušterače što proizvode hormon inzulin ili kao posljedica rezistencije tkiva na inzulin. Obilježen je relativnim ili apsolutnim manjkom inzulina s posljedičnom hiperglikemijom, koja s vremenom može dovesti do oštećenja organskih sustava. Ovisno o tome je li riječ o rezistenciji (neosjetljivosti) tkiva na inzulin ili potpunom uništenju beta-stanica, razlikujemo dva tipa dijabetesa: tip 1 ili dijabetes ovisan o inzulinu i tip 2 ili dijabetes neovisan o inzulinu. Tip 1 najčešće se javlja u ranijoj životnoj dobi (oko 12 godina) dok tip dva nastaje kasnije, poslije 40. Iako se točni uzroci ove bolesti još uvijek ne znaju smatra se da za nastanak važnu ulogu igraju nasljedne osobine, loša prehrana i okoliš (npr. virusna infekcija gušterače).Diabetes is for now incurable chronic disease which appears as a result of damage of betacells which produce hormone insulin or as a result of tissue resistance to that hormone.It is marked by absolute or relative deficiency of insulin, causing hyperglycemia which can eventually lead to damage of many organic systems. Depending is it a word of tissue resistance or total destruction of beta-cells we distinguish two types: type 1 or insulin dependent and type 2 or insulin independent. Type 1 ussualy occurs in younger age while type 1occurs in the middle age (after 40). Although the precise etiology of diabetes is uncertain reasearchers believe that factors as genetics, poor diet (malnutrition) and environment (virus affecting pancreas) may be the trigger of this disease

Komparativna analiza repetitivnog govora kod osoba sa fluentnim i nefluentnim afazijama

Афазија је термин којим се, примарно, означава губитак или поремећај способности продукције, употребе и разумевања језика. Настаје као последица оштећења мозга које може да обухвати широко дистрибуирану мрежу кортикалних и супкортикалних структура. То је мултимодални поремећај којим могу бити обухваћени сви језички модалитети: аудитивно разумевање, говорење, читање, писање, гестовни говор и језичко мишљење. Међутим, у афазији су, поред језика, оштећене и друге когнитивне функције: памћење, пажња и одређени мисаони процеси, па се афазија може сматрати когнитивним поремећајем. Она спада у ред најкомплекснијих и најтежих поремећаја језичких функација изазваних оштећењем мозга. Од свих когнитивних дефицита узрокованих можданим ударом, на пример, афазија највише осиромашује личност. То може бити изражено у таквом степену да афазична особа осећа као да је изгубила сопствену личност. Предмет овог рада је испитивање способности понављања речи и реченица код афазичних пацијената, а у циљу ближег одређивања природе дефицита репетитивног говора код ове популације. Узорак је чинило пет пацијената са флуентним афазијама и пет пацијената са нефлуентним афазијама. У испитивању је коришћен субтест који садржи понављање речи и реченица из Бостонског дијагностичког теста за афазије (БДАЕ). Резултати су показали да нема разлике у репетитивном говору између флуентних и нефлуентних типова афазије. Закључено је да би мали узорак можда могао бити разлог таквих резултата.Aphasia is a term that primarily refers to the loss or disruption of the ability to produce, use, and understand a language. It occurs as a result of brain damage that can encompass a widely distributed network of cortical and subcortical structures. It is a multimodal disorder that can encompass all language modalities: auditory comprehension, speaking, reading, writing, gestural speech and linguistic thinking. However, in aphasia, in addition to language, other cognitive functions are impaired: memory, attention, and certain thought processes, so aphasia can be considered a cognitive disorder. It is one of the most complex and severe disorders of language function caused by brain damage. Of all the cognitive deficits caused by stroke, for example, aphasia is the most impoverished personality. This can be expressed to such an extent that the aphasic person feels as if he has lost his own personality. The subject of this research is to examine the ability to repeat words and sentences in aphasic patients, with a view to more closely determining the nature of the repetitive speech deficit in this population. The sample consisted of five patients with fluent aphasia and five patients with nonfluent aphasia. The test used a subtest containing repetition of words and sentences from the Boston Diagnostic Aphasia Test (BDAE). The results showed that there was no difference in repetitive speech between fluent and non-fluent types of aphasia. It was concluded that a small sample might be the reason for such results

Gothic Elements in Jane Eyre

How does Charlotte Bronte incorporate elements from Gothic Literature into the novel Jane Eyre

Prisilna razgradnja ljekovitih tvari i farmaceutskih oblika

CILJ ISTRAŽIVANJA Cilj istraživanja bio je napraviti pregled i sažetak smjernica regulatornih tijela o prisilnoj razgradnji kao i detaljan vodič o eksperimentalnom provođenju prisilne razgradnje i razvoju stabilitetno-indikativne analitičke metode. MATERIJALI I METODE U ovom teorijskom specijalističkom radu korištena je dostupna znanstvena literatura o prisilnoj razgradnji i pojmovima vezanim uz prisilnu razgradnju. Pregled literature uključuje publicirane znanstvene članke, najnovija izdanja odabranih knjiga, trenutno važeće verzije smjernica regulatornih tijela, kao i razne elektroničke izvore. RASPRAVA Prema ICH smjernicama prisilna razgradnja definirana je kao izloženost ljekovite tvari ili gotovog farmaceutskog proizvoda uvjetima jačim od ubrzanih stabilitetnih uvjeta. I regulatorna tijela i ostala dosad provedena istraživanja naglašavaju važnost provedbe studije o prisilnoj razgradnji zbog mogućnosti predviđanja dugoročne stabilnosti ljekovite tvari i/ili farmaceutskog oblika na temelju dobivenih rezultata. Smjernice regulatornih tijela daju neke opće preporuke o prisilnoj razgradnji, ali ne daju detaljne i jasne upute kako provoditi studiju. Uvjeti za izvođenje prisilne razgradnje obično uključuju izlaganje reprezentativnih uzoraka ljekovite tvari ili farmaceutskog oblika povišenoj temperaturi, vlazi, fotolizi, kiseloj i lužnatoj hidrolizi i oksidaciji. Za hidrolitičke uvjete najčešće se koristi klorovodična ili sumporna kiselina i natrijev ili kalijev hidroksid, koncentracije 0.1-1 mol/L, a za uvjete oksidacije otopina vodikovog peroksida. Za izloženost fotolitičkim uvjetima većina istraživanja se poziva na ICH poglavlje Q1B dok se za procjenu utjecaja temperature i vlage, razgradnja najčešće provodi na temperaturama od 40°C do 80°C i pri 75%RV ili više. Nastali razgradni produkti, koji mogu, ali ne moraju nastati prilikom izloženosti lijeka uobičajenim dugoročnim stabilitetnim uvjetima, nužni su za razvoj stabilitetno-indikativne metode. ZAKLJUČAK U novije vrijeme prisilna razgradnja postala je najvažniji alat u predviđanju dugoročne stabilnosti lijekova. Iz tog razloga studija prisilne razgradnje trebala bi biti sastavni dio razvojnog procesa svakog farmaceutskog proizvoda.OBJECTIVES The aim of this work is to make a summary of all regulatory guidelines and also a detailed guide of the experimental implementation of forced degradation and development of stability indicating analytical method. MATERIALS AND METHODS In this theoretical specialist thesis, available scientific literature on forced degradation study and the terms associated with it, was used. The literature review includes published scientific articles, latest editions of selected books, current versions of the regulatory guidelines as well as various electronic sources. DISCUSSION Both, regulatories and scientific researches emphasize the importance of conducting forced degradation studies for predicting long-term stability of active drug substances and / or finished products. The regulatory agencies give some general recommendations for conducting forced degradation study but they do not give clear and detailed guidance on how to carry out the forced degradation study. Conditions for conducting forced degradation study usually involve exposure of representative drug substance or pharmaceutical form samples to elevated temperature, humidity, photolysis, acidic and basic hydrolysis, and oxidation. For hydrolytic conditions, hydrochloric or sulfuric acid and sodium or potassium hydroxide, with concentrations in range 0.1-1 mol/L are usually used. For oxidation conditions different concentrations of hydrogen peroxide solution are used. For exposure to photolytic conditions most studies are performed according to ICH Q1B, while exposure to temperature and humidity is usually carried out at temperatures from 40 ° C to 80 ° C and 75% RH or more. Obtained degradations products, which are not neccessary formed during long term stability conditions, are most important part of the development of the stability indicating method. CONCLUSION More recently forced degradation has become the most important tool in predicting the long-term stability of the drug. For this reason, forced degradation studies should be an integral part of the development process of each pharmaceutical product