Refining the hospitalization rate: A mixed methods approach to differentiate primary COVID-19 from incidental cases.

Purpose: Until now, the Hospitalization Rate (HR) served as an indicator (among others) for the COVID-19 associated healthcare burden. To ensure that the HR accomplishes its full potential, hospitalizations caused by COVID-19 (primary cases) and hospitalizations of patients with incidental positive SARS-CoV-2 test results (incidental cases) must be differentiated. The aim of this study was to synthesize the existing evidence on differentiation criteria between hospitalizations of primary cases and incidental cases. Methods: An online survey of the members of the German Network University Medicine (NUM) was conducted. Additionally, senior clinicians with expertise in COVID-19 care were invited for qualitative, semi-structured interviews. Furthermore, a rapid literature review was undertaken on publications between 03/2020 and 12/2022. Results: In the online survey (n=30, response rate 56%), pneumonia and acute upper respiratory tract infections were the most indicative diagnoses for a primary case. In contrast, malignant neoplasms and acute myocardial infarctions were most likely to be associated with incidental cases. According to the experts (n=6), the diagnosis, ward, and type of admission (emergency or elective), low oxygen saturation, need for supplemental oxygen, and initiation of COVID-19 therapy point to a primary case. The literature review found that respiratory syndromes and symptoms, oxygen support, and elevated levels of inflammatory markers were associated with primary cases. Conclusion: There are parameters for the differentiation of primary from incidental cases to improve the objective of the HR. Ultimately, an updated HR has the potential to serve as a more accurate indicator of the COVID-19 associated healthcare burden.

[Relevance of health geographic research for dermatology]. / Bedeutung der gesundheitsgeografischen Forschung für die Dermatologie.

The association between geographic and medical aspects is a well-known phenomenon, which also occurs in dermatological research. This article reviews the field of health geography, the history of the association between spatial location and health, and focuses on current areas of research. Research focusing on explaining regional variations in health refer to individual aspects and needs, population factors, environmental factors, and health care delivery structures in specific regions, as well as the interaction between them. Regional healthcare research is primarily concerned with access to health services and on the utilisation of those services. Methodologically, the analysis of geodata and the application of geographic information systems (GIS) and spatial modelling play a major role in this field. Dermatological research and dermatological practice can benefit from the findings of the regional analysis of access, utilisation, and variations in order to obtain a more detailed picture of care and thus to optimise care.

LIGHT/LTßR signaling regulates self-renewal and differentiation of hematopoietic and leukemia stem cells.

The production of blood cells during steady-state and increased demand depends on the regulation of hematopoietic stem cell (HSC) self-renewal and differentiation. Similarly, the balance between self-renewal and differentiation of leukemia stem cells (LSCs) is crucial in the pathogenesis of leukemia. Here, we document that the TNF receptor superfamily member lymphotoxin-ß receptor (LTßR) and its ligand LIGHT regulate quiescence and self-renewal of murine and human HSCs and LSCs. Cell-autonomous LIGHT/LTßR signaling on HSCs reduces cell cycling, promotes symmetric cell division and prevents primitive HSCs from exhaustion in serial re-transplantation experiments and genotoxic stress. LTßR deficiency reduces the numbers of LSCs and prolongs survival in a murine chronic myeloid leukemia (CML) model. Similarly, LIGHT/LTßR signaling in human G-CSF mobilized HSCs and human LSCs results in increased colony forming capacity in vitro. Thus, our results define LIGHT/LTßR signaling as an important pathway in the regulation of the self-renewal of HSCs and LSCs.

Analysis of soluble or titanium dioxide derived titanium levels in human whole blood: consensus from an inter-laboratory comparison.

Exposure to titanium (Ti), via the ingestion of pigment grade Ti dioxide (TiO2), is commonplace for westernised populations. It may also occur as a consequence of metal ion leaching in subjects bearing Ti-containing implants. Accurate exposure analysis requires fit-for-purpose analytical methodology, especially for true measures of baseline levels. Inductively coupled plasma (ICP) techniques are, mainly, now used for bio-analysis of Ti. Since whole blood reference materials, certified for natural low levels of Ti, are not currently available, we undertook an inter-laboratory comparison of pooled human blood from fasted volunteers ±low level (+∼2.5 µg L-1) or high level (+10-20 µg L-1) spikes of soluble Ti or TiO2 particles. Seven established laboratories were enrolled to analyse the samples using ICP based techniques, which included at least one of ICP optical emission spectrometry (ICP-OES), high resolution ICP mass spectrometry (HR-ICP-MS), triple quadrupole ICP-MS (ICP-MS/MS) or single quadrupole ICP-MS (SQ-ICP-MS). Five laboratories diluted the blood for analysis whilst two performed acid digestion. Overall, we showed that the laboratories could, mostly, quantitatively detect modest levels of spiked Ti in blood. Markedly varying levels of Ti, however, were reported for the same baseline pooled sample (0.4-24.6 µg L-1) and, in this study, specificity was poor for SQ-ICP-MS. Digestion of samples caused sample contamination compromising limits of detection and accuracy, whilst simple dilution had no such problem, and remained linear in response for spikes with ionic and TiO2 particles. We conclude that measuring baseline levels of Ti in whole blood is challenging but should be readily achievable down to 0.5-1.5 µg L-1, if sample preparation avoids contamination and instrument techniques are used that negate polyatomic or isobaric interferences from the sample matrix. We also remind those relying upon Ti bio-analytical data for their experimental outcomes that (a) spiking and recovery experiments provide information only on linearity of detection but not at all on accuracy as this will not detect constant positive errors and that (b) biological standard materials for Ti generally contain high levels of the analyte and tend to mask baseline analytical errors. Caution may be required in interpreting the findings of some published Ti/TiO2 bio-exposure studies.

[Quality in Revision Arthroplasty: A Comparison between Claims Data Analysis and External Quality Assurance]. / Ergebnisqualität in der Revisionsendoprothetik: Eine Analyse von Routinedaten mit dem Vergleich zur externen Qualitätssicherung.

BACKGROUND: External quality assurance for revisions of total knee arthroplasty (TKA) and total hip arthroplasty (THA) are carried out through the AQUA institute in Germany. Data are collected by the providers and are analyzed based on predefined quality indicators from the hospital stay in which the revision was performed. The present study explores the possibility to add routine data analysis to the existing external quality assurance (EQS). Differences between methods are displayed. The study aims to quantify the benefit of an additional analysis that allows patients to be followed up beyond the hospitalization itself. MATERIAL AND METHODS: All persons insured in an AOK sickness fund formed the population for analysis. Revisions were identified using the same algorithm as the existing external quality assurance. Adverse events were defined according to the AQUA indicators for the years 2008 to 2011.The hospital stay in which the revision took place and a follow-up of 30 days were included. For re-operation and dislocation we also defined a 365 days interval for additional follow-up. The results were compared to the external quality control reports. RESULTS: Almost all indicators showed higher events in claims data analysis than in external quality control. Major differences are seen for dislocation (EQS SD: 1.87 vs. claims data [cd] SD: 2.06 %, cd+30 d: 2.91 %, cd+365 d: 7.27 %) and reoperation (hip revision: EQS SD: 5.88 % vs. claims data SD: 8.79 % cd+30 d: 9.82 %, cd+365 d: 15.0 %/knee revision: EQS SD: 3.21 % vs. claims data SD: 4.07 %, cd+30 d: 4.6 %, cd+365 d: 15.43 %). Claims data could show additional adverse events for all indicators after the initial hospital stay, rising to 77 % of all events. CONCLUSIONS: The number of adverse events differs between the existing external quality control and our claims data analysis. Claims data give the opportunity to complement existing methods of quality control though a longer follow-up, when many complications become evident.

Role of protein kinase C δ in apoptotic signaling of oxidized phospholipids in RAW 264.7 macrophages.

The oxidized phospholipids (oxPl) 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC) and 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC) are cytotoxic components of oxidized LDL (oxLDL). Sustained exposure to oxLDL or isolated oxPl induces apoptotic signaling in vascular cells, which is a hallmark of the late phase of atherosclerosis. Activation of sphingomyelinase, the coordinate formation of ceramide and activation of caspase 3/7 as well as the activation of stress-associated kinases are causally involved in this process. Here, we provide evidence for a role of PKCδ in oxPl cytotoxicity. Silencing of the enzyme by siRNA significantly reduced caspase 3/7 activation in RAW 264.7 macrophages under the influence of oxPl. Concomitantly, PKCδ was phosphorylated as a consequence of cell exposure to PGPC or POVPC. Single molecule fluorescence microscopy provided direct evidence for oxPl-protein interaction. Both oxPl recruited an RFP-tagged PKCδ to the plasma membrane in a concentration-dependent manner. In addition, two color cross-correlation number and brightness (ccN&B) analysis of the molecular motions revealed that fluorescently labeled PGPC or POVPC analogs co-diffuse and are associated with the fluorescent protein kinase in live cells. The underlying lipid-protein interactions may be due to chemical bonding (imine formation between the phospholipid aldehyde POVPC with protein amino groups) and physical association (with POVPC or PGPC). In summary, our data supports the assumption that PKCδ acts as a proapototic kinase in oxPl-included apoptosis of RAW 264.7 macrophages. The direct association of the bioactive lipids with this enzyme seems to be an important step in the early phase of apoptotic signaling.

Dementia in the USA: state variation in prevalence.

BACKGROUND: The number of dementia patients will increase over the next decades. However, we lack information on the geographic distribution of these patients. We aimed to describe the variation of dementia prevalence and to then compare the observed to expected prevalence. METHODS: This study is based on a 20% sample of Medicare beneficiaries in 2008. The crude dementia prevalence was calculated and age/sex standardized to the US population for states. We used the World Alzheimer Report 2009 prevalence to compare estimates. RESULTS: 4.8 million persons were included. The adjusted prevalence is 8.24%, varying from 5.96 to 9.55% across states. The diagnosed prevalence is lower than the expected in most states. Overall, we estimate over 100 000 undiagnosed dementia patients in Medicare. CONCLUSIONS: The high state variation suggests that the number of diagnosed dementia cases does not fall evenly across all states and hence may require different levels of state-level planning.

Optimizing rapid solvent exchange preparation of multilamellar vesicles.

We have enhanced the rapid solvent exchange (RSE) apparatus by adding controls in temperature, evacuation speed and vortex velocity. Following published protocols yielded vesicles of diverse size and lamellarity as detected by differential scanning calorimetry, photon correlation spectroscopy and X-ray experiments. To optimize the net production of multilamellar vesicles (MLVs) we varied in addition to vortex and evacuation speed lipid and organic solvent concentration, as well as composition of the aqueous medium. Reducing vortexing frequencies and speed of degassing were most beneficial for the yield in MLVs. Additionally also high lipid concentrations and organic solvent/buffer ratios supported MLV formation. To explain our findings we hypothesize on the role of microscopic instabilities on the aqueous phase, which may act as molds for vesicle formation.

[Morbidity differences according to nursing stage and nursing setting in long-term care patients: Results of a claims data based study]. / Morbiditätsunterschiede bei Pflegebedürftigen in Abhängigkeit von Pflegesektor und Pflegestufe: Eine Untersuchung auf der Basis von Abrechnungsdaten der Gesetzlichen Krankenversicherung.

BACKGROUND: We analyzed the differences in morbidity patterns of chronic diseases between long-term care dependent persons in nursing homes compared to those dwelling in the community. We also investigated morbidity differences between long-term care need stages in Germany. MATERIALS AND METHODS: The study included claims data of one nationwide operating statutory health insurance in 2006. Inclusion criteria were age ≥ 65 years, minimum 1 out of 46 diagnoses in at least 3 quarters of the year (n = 8,670). A comparison population was formed with n = 114,962. Prevalences, relative risks, and odds ratios for the risk of nursing home care were calculated. RESULTS: In the bivariate analysis, only three chronic diseases - dementia, urinary incontinence, and chronic heart failure - showed a higher risk for nursing home care. Regression analysis revealed that only dementia showed higher odds related to the stage of nursing needs. CONCLUSION: Among the chronic diseases, only dementia shows a substantially elevated risk for nursing home care. Risk studies on other chronic diseases associated with higher risks of long-term care dependency and specific intervention strategies aiming at delaying or preventing nursing home admission should be developed.

Genetic variant predicts bevacizumab-induced hypertension in ECOG-5103 and ECOG-2100.

BACKGROUND: Bevacizumab has broad anti-tumour activity, but substantial risk of hypertension. No reliable markers are available for predicting bevacizumab-induced hypertension. METHODS: A genome-wide association study (GWAS) was performed in the phase III bevacizumab-based adjuvant breast cancer trial, ECOG-5103, to evaluate for an association between genotypes and hypertension. GWAS was conducted in those who had experienced systolic blood pressure (SBP) >160 mm Hg during therapy using binary analysis and a cumulative dose model for the total exposure of bevacizumab. Common toxicity criteria (CTC) grade 3-5 hypertension was also assessed. Candidate SNP validation was performed in the randomised phase III trial, ECOG-2100. RESULTS: When using the phenotype of SBP>160 mm Hg, the most significant association in SV2C (rs6453204) approached and met genome-wide significance in the binary model (P=6.0 × 10(-8); OR=3.3) and in the cumulative dose model (P=4.7 × 10(-8); HR=2.2), respectively. Similar associations with rs6453204 were seen for CTC grade 3-5 hypertension but did not meet genome-wide significance. Validation study from ECOG-2100 demonstrated a statistically significant association between this SNP and grade 3/4 hypertension using the binary model (P-value=0.037; OR=2.4). CONCLUSIONS: A genetic variant in SV2C predicted clinically relevant bevacizumab-induced hypertension in two independent, randomised phase III trials.

[The epidemiology of chronic diseases and long-term care: results of a claims data-based study]. / Die Epidemiologie von chronischen Krankheiten und Pflegebedürftigkeit : Eine Untersuchung auf der Basis von Abrechnungsdaten der gesetzlichen Krankenversicherung.

BACKGROUND: It is generally assumed that chronic diseases and multimorbidity increase the risk of long-term care. Nevertheless, a systematic study on the nature and the prevalence of those diseases associated with long-term care has not been yet undertaken in Germany. MATERIALS AND METHODS: The study was perfomed using claims data of one nationwide operating statutory health insurance company in 2006. Inclusion criteria were age ≥ 65 years, minimum of 1 out of 46 diagnoses in a minimum of three quarters of the year (n = 8,678). A comparison group was formed with n = 114,962. We calculated prevalences and relative risks -using nominal regression- to determine influential factors on long-term care. RESULTS: A small number of diseases (e.g. dementia, urinary incontinence, chronic stroke and cardiac insufficiency) show high prevalences (> 20%) among long-term care users and at the same time great prevalence differences between users and non-users CONCLUSION: These data are important for improving medical and nursing care of long-term care users. Further research is needed with regard to the question by which mechanisms those diseases produce disability and frailty, thus leading to long-term care requirements.

Type I interferon signaling genes in recurrent major depression: increased expression detected by whole-blood RNA sequencing.

A study of genome-wide gene expression in major depressive disorder (MDD) was undertaken in a large population-based sample to determine whether altered expression levels of genes and pathways could provide insights into biological mechanisms that are relevant to this disorder. Gene expression studies have the potential to detect changes that may be because of differences in common or rare genomic sequence variation, environmental factors or their interaction. We recruited a European ancestry sample of 463 individuals with recurrent MDD and 459 controls, obtained self-report and semi-structured interview data about psychiatric and medical history and other environmental variables, sequenced RNA from whole blood and genotyped a genome-wide panel of common single-nucleotide polymorphisms. We used analytical methods to identify MDD-related genes and pathways using all of these sources of information. In analyses of association between MDD and expression levels of 13 857 single autosomal genes, accounting for multiple technical, physiological and environmental covariates, a significant excess of low P-values was observed, but there was no significant single-gene association after genome-wide correction. Pathway-based analyses of expression data detected significant association of MDD with increased expression of genes in the interferon α/ß signaling pathway. This finding could not be explained by potentially confounding diseases and medications (including antidepressants) or by computationally estimated proportions of white blood cell types. Although cause-effect relationships cannot be determined from these data, the results support the hypothesis that altered immune signaling has a role in the pathogenesis, manifestation, and/or the persistence and progression of MDD.

High-fidelity Hugoniot analysis of porous materials.

An experimental technique and analysis methodology for obtaining high-fidelity Hugoniot measurements with defined uncertainty bounds on powder compacts using optical velocimetry is presented. Impedance matching is used to calculate the shocked state in the powder from the measured initial compact density, ρ(00), impact velocity, V(Imp), and shock velocity, U(S). Detailed characterization of the powder thicknesses at precise locations results in improvements in characterization of the initial density state and accurate measurements of the powder thickness at locations corresponding to shock velocity measurements. These measurements result in high accuracies in the equilibrium Hugoniot state and reduced uncertainties in the measured and calculated Hugoniot parameters. Assumptions in this analysis include a constant and homogeneous initial porous density, and steady state wave propagation. The approach is applied to a system of CeO(2) powder pressed to 4.0 g/cm(3) (55% theoretical maximum density), and results indicate a complex dynamic response.

Enrichment of cis-regulatory gene expression SNPs and methylation quantitative trait loci among bipolar disorder susceptibility variants.

We conducted a systematic study of top susceptibility variants from a genome-wide association (GWA) study of bipolar disorder to gain insight into the functional consequences of genetic variation influencing disease risk. We report here the results of experiments to explore the effects of these susceptibility variants on DNA methylation and mRNA expression in human cerebellum samples. Among the top susceptibility variants, we identified an enrichment of cis regulatory loci on mRNA expression (eQTLs), and a significant excess of quantitative trait loci for DNA CpG methylation, hereafter referred to as methylation quantitative trait loci (mQTLs). Bipolar disorder susceptibility variants that cis regulate both cerebellar expression and methylation of the same gene are a very small proportion of bipolar disorder susceptibility variants. This finding suggests that mQTLs and eQTLs provide orthogonal ways of functionally annotating genetic variation within the context of studies of pathophysiology in brain. No lymphocyte mQTL enrichment was found, suggesting that mQTL enrichment was specific to the cerebellum, in contrast to eQTLs. Separately, we found that using mQTL information to restrict the number of single-nucleotide polymorphisms studied enhances our ability to detect a significant association. With this restriction a priori informed by the observed functional enrichment, we identified a significant association (rs12618769, P(bonferroni)<0.05) from two other GWA studies (TGen+GAIN; 2191 cases and 1434 controls) of bipolar disorder, which we replicated in an independent GWA study (WTCCC). Collectively, our findings highlight the importance of integrating functional annotation of genetic variants for gene expression and DNA methylation to advance the biological understanding of bipolar disorder.

Variation in antibiotic prescriptions: is area deprivation an explanation? Analysis of 1.2 million children in Germany.

PURPOSE: Inadequate use of antibiotics can lead to problems such as resistance. Overuse is especially a problem for children, since they are more affected by acute (often virus-caused) infections. While the problem has been addressed internationally over the past several years, regional variations in prescriptions are striking. Therefore, the present study aims to analyze regional variations in antibiotic prescription on a district level in Germany and tries to identify reasons for those variations through adding possible influencing factors to the analysis on individual and district levels. METHODS: We analyzed 1.2 million children insured in a German health insurance fund. Antibiotic prescriptions were quantified in 2010 and reasons for prescriptions were analyzed in multilevel regressions based on the district of residence, regional deprivation, and age and sex of the child. RESULTS: Thirty-six percent of all children aged 0-17 years received an antibiotic prescription in 2010. In the south, prevalences are generally lower, and also to the very north. The highest prevalences are found in the close-to-border districts in the west, as well as in a band throughout the middle of Germany, in rather low population density areas. Regional variation in the prevalence range from 19 to 53 % between districts. Regional deprivation can explain part of this variation. CONCLUSIONS: Including area deprivation measures helped identify an influence of especially regional income and occupational deprivation on antibiotic prescriptions for children. Regional analysis such as this can help identify specific regions and groups of persons to address information programs on the risks of preventable antibiotic consumption and alternative treatment methods.

A genome-wide association study of alcohol-dependence symptom counts in extended pedigrees identifies C15orf53.

Several studies have identified genes associated with alcohol-use disorders (AUDs), but the variation in each of these genes explains only a small portion of the genetic vulnerability. The goal of the present study was to perform a genome-wide association study (GWAS) in extended families from the Collaborative Study on the Genetics of Alcoholism to identify novel genes affecting risk for alcohol dependence (AD). To maximize the power of the extended family design, we used a quantitative endophenotype, measured in all individuals: number of alcohol-dependence symptoms endorsed (symptom count (SC)). Secondary analyses were performed to determine if the single nucleotide polymorphisms (SNPs) associated with SC were also associated with the dichotomous phenotype, DSM-IV AD. This family-based GWAS identified SNPs in C15orf53 that are strongly associated with DSM-IV alcohol-dependence symptom counts (P=4.5 × 10(-8), inflation-corrected P=9.4 × 10(-7)). Results with DSM-IV AD in the regions of interest support our findings with SC, although the associations were less significant. Attempted replications of the most promising association results were conducted in two independent samples: nonoverlapping subjects from the Study of Addiction: Genes and Environment (SAGE) and the Australian Twin Family Study of AUDs (OZALC). Nominal association of C15orf53 with SC was observed in SAGE. The variant that showed strongest association with SC, rs12912251 and its highly correlated variants (D'=1, r(2) 0.95), have previously been associated with risk for bipolar disorder.

Convergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk prediction.

We have used a translational convergent functional genomics (CFG) approach to identify and prioritize genes involved in schizophrenia, by gene-level integration of genome-wide association study data with other genetic and gene expression studies in humans and animal models. Using this polyevidence scoring and pathway analyses, we identify top genes (DISC1, TCF4, MBP, MOBP, NCAM1, NRCAM, NDUFV2, RAB18, as well as ADCYAP1, BDNF, CNR1, COMT, DRD2, DTNBP1, GAD1, GRIA1, GRIN2B, HTR2A, NRG1, RELN, SNAP-25, TNIK), brain development, myelination, cell adhesion, glutamate receptor signaling, G-protein-coupled receptor signaling and cAMP-mediated signaling as key to pathophysiology and as targets for therapeutic intervention. Overall, the data are consistent with a model of disrupted connectivity in schizophrenia, resulting from the effects of neurodevelopmental environmental stress on a background of genetic vulnerability. In addition, we show how the top candidate genes identified by CFG can be used to generate a genetic risk prediction score (GRPS) to aid schizophrenia diagnostics, with predictive ability in independent cohorts. The GRPS also differentiates classic age of onset schizophrenia from early onset and late-onset disease. We also show, in three independent cohorts, two European American and one African American, increasing overlap, reproducibility and consistency of findings from single-nucleotide polymorphisms to genes, then genes prioritized by CFG, and ultimately at the level of biological pathways and mechanisms. Finally, we compared our top candidate genes for schizophrenia from this analysis with top candidate genes for bipolar disorder and anxiety disorders from previous CFG analyses conducted by us, as well as findings from the fields of autism and Alzheimer. Overall, our work maps the genomic and biological landscape for schizophrenia, providing leads towards a better understanding of illness, diagnostics and therapeutics. It also reveals the significant genetic overlap with other major psychiatric disorder domains, suggesting the need for improved nosology.

Small- and wide-angle X-ray scattering (SWAXS) for quantification of aspirin content in a binary powder mixture.

This article presents a novel application of small and wide angle X-ray scattering (SWAXS) in the assessment of aspirin and lactose content in a binary pharmaceutical powder formulation. It is shown that the content correlates with the intensity of the SAXS signal and the intensity of polymorph fingerprints in the WAXS spectra that are collected from the same samples. Because the polymorph WAXS fingerprints and the SAXS signal are two independent characteristics of the same sample, simultaneous SWAXS analysis provides the basis for a dual independent assessment of the same contents.

Genome-wide linkage analysis of 972 bipolar pedigrees using single-nucleotide polymorphisms.

Because of the high costs associated with ascertainment of families, most linkage studies of Bipolar I disorder (BPI) have used relatively small samples. Moreover, the genetic information content reported in most studies has been less than 0.6. Although microsatellite markers spaced every 10 cM typically extract most of the genetic information content for larger multiplex families, they can be less informative for smaller pedigrees especially for affected sib pair kindreds. For these reasons we collaborated to pool family resources and carried out higher density genotyping. Approximately 1100 pedigrees of European ancestry were initially selected for study and were genotyped by the Center for Inherited Disease Research using the Illumina Linkage Panel 12 set of 6090 single-nucleotide polymorphisms. Of the ~1100 families, 972 were informative for further analyses, and mean information content was 0.86 after pruning for linkage disequilibrium. The 972 kindreds include 2284 cases of BPI disorder, 498 individuals with bipolar II disorder (BPII) and 702 subjects with recurrent major depression. Three affection status models (ASMs) were considered: ASM1 (BPI and schizoaffective disorder, BP cases (SABP) only), ASM2 (ASM1 cases plus BPII) and ASM3 (ASM2 cases plus recurrent major depression). Both parametric and non-parametric linkage methods were carried out. The strongest findings occurred at 6q21 (non-parametric pairs LOD 3.4 for rs1046943 at 119 cM) and 9q21 (non-parametric pairs logarithm of odds (LOD) 3.4 for rs722642 at 78 cM) using only BPI and schizoaffective (SA), BP cases. Both results met genome-wide significant criteria, although neither was significant after correction for multiple analyses. We also inspected parametric scores for the larger multiplex families to identify possible rare susceptibility loci. In this analysis, we observed 59 parametric LODs of 2 or greater, many of which are likely to be close to maximum possible scores. Although some linkage findings may be false positives, the results could help prioritize the search for rare variants using whole exome or genome sequencing.

Exclusion of Class III malocclusion candidate loci in Brazilian families.

The role played by genetic components in the etiology of the Class III phenotype, a class of dental malocclusion, is not yet understood. Regions that may be related to the development of Class III malocclusion have been suggested previously. The aim of this study was to search for genetic linkage with 6 microsatellite markers (D1S234, D4S3038, D6S1689, D7S503, D10S1483, and D19S566), near previously proposed candidate regions for Class III. We performed a two-point parametric linkage analysis for 42 affected individuals from 10 Brazilian families with a positive Class III malocclusion segregation. Analysis of our data indicated that there was no evidence for linkage of any of the 6 microsatellite markers to a Class III locus at = zero, with data supporting exclusion for 5 of the 6 markers evaluated. The present work reinforces that Class III is likely to demonstrate locus heterogeneity, and there is a dependency of the genetic background of the population in linkage studies.