Psoriasis is a chronic, clinically heterogeneous, skin condition that affects approximately 2% of the general population. In 1985, Henseler and Christophers, classified psoriasis into early onset (EOP; age at onset ≤40 years-y) and late onset disease (LOP; age at onset >40 y). Previous research suggests that there are genetic and immunological differences between EOP and LOP. In particular, the major genetic determinant for psoriasis, the human leukocyte antigen (HLA)-Cw6 allele, occurs more frequently in EOP (55-80%) compared to LOP (15-20%) patients. Epidermal Langerhans’ cells (LC) migration is also different in these 2 subtypes of psoriasis. The primary aim of this thesis was to further explore the clinical, histological and immunohistochemical (IHC) differences between EOP and LOP. We compared clinical characteristics in a total of 497 subjects, including 340 psoriasis patients (108 recruited prospectively; 76 EOP and 32 LOP, mean age of onset 20.3±9.9 and 55.6±7y respectively, and 232 retrospectively; 202 EOP and 30 LOP, mean age of onset 20.7±9.9 and 55.2±7.2y respectively) and 157 controls (mean age 66±11.2y). Information on demographics, family history of psoriasis, clinical features, treatment and co-morbidities were recorded. Patients were also assessed for health-related quality of life and psychological distress. A total of 31 psoriasis patients, ≥ 50y of age, participated in the histological and IHC evaluation; 17 EOP and 14 LOP, mean age of onset 21.1±8.5 and 55.4±7.7y respectively. Skin biopsies were taken from involved (PP) and uninvolved (PN) skin and stained with haematoxylin and eosin (H&E) and IHC antibodies against various T-cell (CD3, CD4, and CD8) and LC (CD1α) markers. The H&E parameters (morphological and inflammatory) were graded with the use of a study specific histological score, whilst IHC positive epidermal cells were counted per microscopic field at 200X magnification. The dermal IHC infiltrate was assessed with a semi-quantitative (0-3) scale. Gender, body mass index, disease duration and severity, diagnosed hypertension and dyslipidemia were treated as covariates. The clinical data showed that LOP patients had a lower likelihood of having a positive family history of psoriasis (62% of EOP versus 35.6% of LOP patients; chi square-x2, P=0.001). In addition, patients with EOP parent(s) were 91% less likely to develop LOP than EOP (odds ratio-OR=0.093, P=0.025, 95% confidence interval-CI 0.012-0.74). Moreover, compared to LOP, EOP patients had a more severe disease (x2, P=0.021), usually requiring 3rd line treatments (x2; P=0.010). They also experienced frequent flares, following upper respiratory tract infections (x2, P=0.049). When data were segregated by age (≥50years) and after accounting for covariates, we observed that, compared to the non-psoriasis population, LOP patients were approximately 3 times more likely to develop type 2 Diabetes Mellitus (OR=2.56, P=0.05, 95% CI 1.01-6.54), whilst, EOP subjects were 98% less likely to develop autoimmune thyroiditis (OR=0.025, P=0.02, 95% CI 0.001-0.55). Psychologically, LOP patients were found to be a clinically more anxious group compared to EOP (t-test, P=0.006). Microscopically, the results from the H&E study showed an increased total inflammatory infiltrate in LOP, PP sections compared to EOP, PP ones (t-test, P=0.028). With IHC stains, we observed that in the epidermis of LOP PP, there was a significantly higher count of CD4+ cells; mean CD4+ in LOP of 15.1 ± 6.2 versus 6.7±4.6 in EOP (Analysis of variance-ANOVA, P<0.001). This subsequently led to a higher epidermal CD4+/CD8+ ratio of 1.3 in the LOP versus 0.5 for the EOP sections (ANOVA, P=0.002). In the PP dermis, CD4+ were also more abundant in the LOP tissue (x2, P=0.049). To assess whether these CD4+ cells were either T-lymphocytes or LC, we examined for differences in the CD3+ and CD1α+ cells. The mean epidermal CD3+ tended to be higher in LOP PP sections; mean epidermal CD3+ in the LOP 42.8 ± 13.3 versus 31.7 ± 17.5 in the EOP group (ANOVA, P= 0.061), while the dermal infiltrate showed a similar pattern (x2,P=0.067). Finally, there was no difference in epidermal and dermal CD1α+ and CD8+ cells in PP between EOP and LOP sections. These data indicate differences in clinical phenotype, heritability, comorbidities and immunopathomechanism between EOP and LOP. Taken together they provide further evidence that EOP and LOP may be different diseases.

Late-onset hypogonadism (LOH) is a pathological disorder that develops in males over the age of 40 and is diagnosed upon strict criteria that requires that the individual have total serum testosterone (T) below the normal limits as well as three symptoms of sexual dysfunction. Recommended therapy for young males with hypogonadism is testosterone replacement therapy (TRT). Treatment of LOH with TRT has increased significantly in the past several years, but studies showing adverse risks associated with TRT have led to a growing concern about the safety of such a treatment. This systematic review will give an overview of the pathology of LOH, clinical diagnosis of LOH, and comorbidities associated with this dysfunction. Benefits of TRT in elderly hypogonadal men have included improvement in cardiovascular function, reduced all-cause mortality, increased sexual function, increased bone mineral density, improved body composition, increased muscle strength, improved quality of life, and improvement in metabolic parameters. However, risks associated with TRT have included infertility, worsening lipid panel parameters, polycythemia, increased risk of prostate cancer, and in some cases, increased risk of adverse cardiovascular events.

Although multiple susceptibility loci for late-onset Alzheimer's disease (LOAD) have been identified, a large portion of the genetic risk for this disease remains unexplained. LOAD risk may be associated with single-nucleotide polymorphisms responsible for changes in gene expression (eSNPs). To detect eSNPs associated with LOAD, we integrated data from LOAD genome-wide association studies and expression quantitative trait loci using Sherlock (a Bayesian statistical method). We identified a cis-regulatory eSNP (rs2927438) located on chromosome 19q13.32, for which subsequent analyses confirmed the association with both LOAD risk and the expression level of several nearby genes. Importantly, rs2927438 may represent an APOE-independent LOAD eSNP according to the weak linkage disequilibrium of rs2927438 with the 2 polymorphisms (rs7412 and rs429358) defining the APOE-ε2, -ε3, and -ε4 alleles. Furthermore, rs2927438 does not influence chromatin interaction events at the APOE locus or cis-regulation of APOE expression. Further exploratory analysis revealed that rs2927438 is significantly associated with tau levels in the cerebrospinal fluid. Our findings suggest that rs2927438 may confer APOE-independent risk for LOAD.

Um die Mortalität und Morbidität von Sepsisepisoden bei Frühgeborenen zu verbessern, kommt einer frühen und sicheren Diagnosestellung besonderes Interesse entgegen. In dieser Arbeit wurde untersucht, inwiefern durch eine Analyse einfacher klinischer Symptome die Wahrscheinlichkeit einer Sepsisepisode korrekt vorausgesagt werden kann. In einer prospektiven Studie wurden in 83 Verdachtsmomenten einer Sepsis bei 67 Frühgeborenen die Basisdaten (Geburtsalter, Geburtsgewicht, etc.), die klinischen (kardiovaskuläre, pulmonale, gastrale und neurologische Symptome) und die paraklinischen (CRP, Blutkulturen, etc.) Variablen analysiert. In 39 Verdachtsmomenten konnte eine Sepsis bestätigt werden, darunter koagulase-negative Staphylokokken als häufigster Erreger. In 44 Fällen wurde keine Sepsis entdeckt. Die Studie zeigte, dass kardiovaskuläre Symptome bei Frühgeborenen frühzeitig auf eine Sepsis hinweisen können. Ein Novum stellte hierbei die Messung einer zentral-peripheren Temperaturdifferenz (cpTD) dar, deren Erhöhung mit einer deutlichen höheren Wahrscheinlichkeit für das Vorliegen einer Sepsis assoziiert war. Sie bietet eine kostengünstige, nicht-invasive und kontinuierlich messbare Methode zur verbesserten Diagnosestellung einer Neugeborenensepsis.:1. Einleitung 2. Hintergründe 3. Ableitung der Fragestellung (inklusive Hypothesen) 4. Publikation 5. Zusammenfassung der Arbeit 6. Aufnahme in die aktuellen Leitlinien 7. Literaturverzeichnis / The study investigated the association between clinical symptoms and late-onset sepsis (LOS) in preterm infants with the aim of identifying a non-invasive tool for the early detection of LOS. This was a prospective study of 83 episodes of suspected LOS in 67 preterm infants. At the time LOS was suspected, we recorded a standardized set of clinical symptoms. A diagnosis of “clinical LOS” (Clin-LOS), “culture-proven LOS” (Prov-LOS) or “LOS not present” (No-LOS) was made on the basis of C-reactive protein (CrP) and blood culture results. We examined univariable associations between clinical signs and LOS using odds ratio (OR) analysis and then adjusted the odds ratio (adOR) through binary regression analysis. Clin-LOS was diagnosed in 20/83 episodes, 19 cases were found to have Prov-LOS. Clinical signs which had a significant association with Clin-LOS were capillary refill time > 2 s (OR 2.9) and decreased responsiveness (OR 5.2), whereas there was a negative association between gastric residuals and LOS (OR 0.35). However, the most marked association was found for a greater central-peripheral temperature difference (cpTD) > 2 °C (OR 9). In Prov-LOS an increased heart rate (OR 3.1), prolonged capillary refill time (OR 3.3) and again an increased cpTD (OR 16) had a significant association with LOS, whereas gastric residuals were negatively associated (OR 0.29). Regression analysis showed that cpTD was the most striking clinical sign associated with both Clin- (adOR 6.3) and Prov-LOS (adOR 10.5). Conclusions: Prolonged capillary refill time and – more impressive – elevated cpTD were the most useful clinical symptoms for detection of LOS in preterm infants. We especially suggest using cpTD as a predictor of LOS. It is a cheap, non-invasive and readily available tool for daily routines.:1. Einleitung 2. Hintergründe 3. Ableitung der Fragestellung (inklusive Hypothesen) 4. Publikation 5. Zusammenfassung der Arbeit 6. Aufnahme in die aktuellen Leitlinien 7. Literaturverzeichnis

Bakgrund Antalet personer som diagnostiserats med ADHD har ökat stadigt under de senaste 15 åren. Det har visat sig att många har fått diagnosen först som vuxna. Under senare år har forskning visat upplevelse av lägre livskvalitet hos vuxna med ADHD samt flera konsekvenser av obehandlad ADHD som skilsmässa, ökad risk för missbruk, bilolyckor, olycksfall, depression, ångest och suicid. Syfte Syftet med litteraturstudien var att sammanställa upplevelser och erfarenheter av ADHD hos personer som fått diagnosen i vuxen ålder. Metod Litteraturstudie med kvalitativ design. Med ett perspektiv utifrån vuxna med ADHD har totalt tio vetenskapliga artiklar från databaserna PsycInfo och Cinahl granskats. Data extraherades, översattes, kondenserades, kodades och tematiserades utifrån grundläggande innehållsanalys. Resultat Analysen av studiernas resultat mynnade ut i tre huvudteman: ADHD påverkade livet som beskriver påverkan av ADHD, Diagnosens betydelse och krokiga väg berättar om tankar och känslor av att få diagnos, samt Erfarenheter av strategi, vård och behandling som skildrar hanteringen av symtom och svårigheter samt upplevelser av erbjuden vård. Slutsats Upplevelser av symtom och svårigheter relaterat till ADHD kan skilja stort mellan människor och kön. Något som måste förstås för att möjliggöra ett arbete utifrån personcentrerad omvårdnad. Stigma och negativa upplevelser av vården ses orsakas av bristande förståelse och okunskap. Varför vikten av attitydförändring i samhället ses som avgörande för god livskvalité och bra bemötande. En kunskapslucka som sågs var kvinnors upplevelse av orsak till senare diagnos, här behövs fortsatt forskning. / Background The number of people diagnosed with ADHD has increased steadily over the past 15 years. It has been shown that many have been diagnosed first as an adult. In recent years, research has shown the experience of a lower quality of life in adults with ADHD as well as several consequences of untreated ADHD such as divorce, increased risk of addiction, car accidents, accidental injuries, depression, anxiety, and suicide. Aim The aim of the literature study was to compile experiences of ADHD in people who received the diagnosis in adulthood. Method Literature review with qualitative design. Based on the perspective of adults with ADHD, a total of ten scientific articles from the PsycInfo and Cinahl databases were reviewed. Data were extracted, translated, condensed, coded and thematized based on basic content analysis. Results The analysis of the results of the studies resulted in three main themes: ADHD affected life which describes the impact of ADHD, The significance of the diagnosis and the winding road talks about thoughts and feelings of being diagnosed, and Experiences of strategy, care and treatment which depicts the coping strategies of symptoms and difficulties as well as experiences of offered care. Conclusion Experiences of symptoms and difficulties related to ADHD can differ greatly between people and gender. Something that has to be understood in order to enable work based on person-centred care. Stigma and negative experiences of healthcare are seen to be caused by lack of understanding and unawareness. Why the importance of attitude change in society is seen as crucial for good quality of life and to be treated well. One knowledge gap that was seen was women's experience of the cause of later diagnosis, here continued research is needed.

Background: Neonatal sepsis is one of the most important causes for elevated morbidity and mor-tality rates in neonatal intensive care units worldwide. While the clinical manifestations of a neo-natal sepsis tend to be nonspecific, its rapid development and life-threatening potential calls for reliable markers for early detection. Methods: We conducted a retrospective single center study including all neonates suspected of having developed a neonatal sepsis within 2013 - 2016. Perinatal and clinical characteristics, as well as microbiological and laboratory findings were evaluated. Neonatal sepsis was either defined as culture proven sepsis (positive blood culture) or clinical sepsis (at least one symptom and elevated C-reative protein (CRP) concentrations within 72h with nega-tive blood culture). We further differentiated between early-onset (EOS) and late-onset (LOS) sepsis. Results: Microbiological colonisation screening frequently did not detect the organism which sub-sequently caused the sepsis. Depending on the age of the newborn with sepsis (EOS or LOS), as-sociations between different anamnestic and clinical factors (prenatal or postnatal ones) were found. Especially the central-peripheral temperature difference showed a strong association to LOS. Laboratory results useful for the early detection of a neonatal sepsis included interleukin-6 (IL-6) and CRP concentrations. Conclusion: Elevated IL-6 >100 ng/l was a strong marker for neonatal sepsis. When choosing the antibiotics for treatment, data from microbiological colonisation screening should be considered, but not solely relied on. Some indicators for infection depended also on postnatal age.:Einführung 1 Definition 1 Sepsis 1 Pathophysiologie der Sepsis 2 Early-onset Sepsis vs. Late-onset Sepsis 4 Klinik und Diagnostik 6 AWMF-Leitlinie „Bakterielle Infektionen bei Neugeborenen“ 10 Mikrobiologisches Kolonisationsscreening 14 Aufgabenstellung und Zielsetzung 16 Patient:innen und Methoden 18 Datenerhebung 18 Gruppenbildung 20 Statistische Analyse 22 Ergebnisse 23 Early-onset Sepsis mit mikrobiologischem Nachweis 23 Early-onset Sepsis mit nur paraklinischem Nachweis 30 Late-onset Sepsis mit mikrobiologischem Nachweis 36 Late-onset Sepsis mit nur paraklinischem Nachweis 44 Diskussion 50 Art der Erreger in Leipzig 50 Mikrobiologisches Kolonisationsscreening 51 Anamnestische und klinische Risikofaktoren 55 Laborchemische Faktoren 60 Aussagekraft der Blutkultur 69 Grenzen der Studie 71 Weiterer Ausblick 72 Zusammenfassung 75 Literaturverzeichnis 78 Abkürzungsverzeichnis 83 Tabellenverzeichnis 85 Abbildungsverzeichnis 86 Erklärung über die eigenständige Abfassung der Arbeit 88 Curriculum vitae 89 Danksagung 91

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Ce travail de recherche vise à évaluer les enjeux éthiques posés par le recours au diagnostic anténatal dans le cadre des maladies génétiques à révélation tardive.Notre première étude a été d’analyser les décisions prises en réunions de Centres Pluridisciplinaires de Diagnostic Prénatal (CPDPN) et, à travers des situations réelles et singulières, relever les éléments de discussion et plus particulièrement ceux pouvant influencer la décision. Nous avons, ensuite réalisé deux enquêtes par questionnaires qui ont permis: 1) D’explorer le point de vue des personnes directement concernées par une telle pathologie (porteurs du gène responsable - malades ou asymptomatiques -, conjoints et/ou parents d’une personne porteuse du gène) ; 2) D’étudier la position des professionnels de la parentalité, travaillant en lien avec un CPDPN, et qui sont décideurs de la recevabilité ou non d’une demande de diagnostic anténatal dans ce contexte.Ce travail a ainsi contribué à faire émerger des questionnements pertinents sur le plan éthique et une réflexion sur de possibles évolutions législatives et sociétales dans ce domaine. / This research carries out with the aim of evaluating the ethical challenges faced by the use of antenatal diagnosis in late-onset genetic diseases.In a first study, we analysed the decisions of Multidisciplinary Centres for Prenatal Diagnosis (MCPD) and, through real and specific situations, we identified the elements for discussion and more particularly the ones that could influence the decision-making process. Then, we conducted two questionnaire surveys that allowed to: 1) Explore the viewpoints of people directly affected by this type of pathology (responsible gene carriers - ill or asymptomatic individuals -, partners and/or parents of gene carriers); 2) Examinate the opinions of professionals, working in association with a CPDPN and who are decision-makers of the acceptability or not for an antenatal diagnosis request in this context.This work has therefore brought out questions on ethics, and views on the potential legal and social developments in this area.

Genetic factors account for about half of Alzheimers Disease (AD) risk and only about a quarter of that heritability is accounted for by known variants. Family based approaches to understanding AD genetics may be an effective way to identify additional risk factors. Here we report the results of whole exome sequencing (WES) and analyses done on pairs of AD affected cousins from 19 families from the Utah Population Database (UPDB) with a statistical excess of AD risk. WES variants passing quality control were additionally filtered by population frequency (minor allele <<> 0.01) and concordance between cousin pairs, resulting in 564 variants shared by at least one pair of cousins. For each of these variants we conducted in depth annotations using Ingenuity Variant Analysis (IVA), Wellderly Data Allele Frequencies, and literature searches. To further aid in variant prioritization we analyzed each variant for association with Age at Onset of AD, AD Risk, CSF AB42, CSF Tau, CSF PTau and Rate of Disease Decline in data from the Alzheimers Disease Genetics Consortium (ADGC) and from the Knight Alzheimers disease research center. Statistical analyses were conducted using PLINK. Twelve variants (rs201665195, rs28933981, rs148294193, rs147599881, rs61729902, rs140129800, rs191804178, rs200290640, rs199752248, rs45541434, rs141402160 and rs140914494) in eight genes (ABCA7, TTR, PELI3, FCHO1, SNAP91, COX6A2, MUC16, PIDD1, SYT5 and NOTCH3) were prioritized using a clear pipeline of IVA filters and the additional analysis information. We propose that these genes and variants are the most interesting for follow-up based on current knowledge.This family-based approach to finding rare AD variants adds to a growing body of research suggesting a role for NOTCH3 in late-onset AD. This approach replicated two known AD risk variants and also implicated novel putative risk AD variants and genes. These results suggest that further application of this method of using pairs of cousins may result in additional insights into AD genetics and the ability to find novel rare, causal AD variants.