'Like going into a chocolate shop, blindfolded': What do people with primary progressive aphasia want from speech and language therapy?

BACKGROUND: Primary progressive aphasia (PPA) describes a group of language-led dementias. PPAs are complex, diverse and difficult to diagnose, and therefore conventional models of aphasia and dementia treatment do not meet their needs. The research evidence on intervention for PPA is developing, but to date there are only a few case studies exploring the experiences of people with PPA (PwPPA) themselves. AIMS: To explore the experiences and opinions of PwPPA and their communication partners (CPs) to understand how speech and language therapy (SLT) services can better meet their needs. METHODS & PROCEDURES: A qualitative research approach was used whereby PwPPA and their friends or family members were recruited to participate in focus groups, via advertisements in the Rare Dementia Support PPA group newsletters. Consenting participants were allocated to attend one of four focus groups hosted on an online video conferencing platform. Participants were asked about their communication difficulties, and how SLT could address these needs. All meetings were transcribed, and data were examined using reflexive thematic analysis. OUTCOMES & RESULTS: Six PwPPA and 14 CPs representing all three PPA variants and mixed PPA participated in the focus groups. Four main themes were identified during the analysis of the focus group discussions: (1) CPs' burden, (2) adjusting to the diagnosis, (3) communication abilities and difficulties and (4) beyond language. A further 10 subthemes were identified. CONCLUSIONS & IMPLICATIONS: This study provides a greater understanding of the experiences and needs of PwPPA and their families in relation to SLT. This work underlines the importance of a person-centred approach that considers the broader needs of both the PwPPA and the people around them. This will enable service providers to deliver SLT that meets the needs of PwPPA and their families and will also inform future research in this field. WHAT THIS PAPER ADDS: What is already known on this subject We know that PwPPA can maintain or even make improvements in word retrieval and speech fluency with SLT exercises. There is also developing evidence of the benefits of interventions such as CP training, communication aid support and other functional interventions. What this paper adds to existing knowledge This study provides an understanding of the experiences and opinions of people living with PPA and their families in relation to SLT. Results demonstrate that PwPPA and their families have to navigate a complex journey, identifying strategies to support communication but also the influence of personality and other cognitive symptoms. SLT was useful, but not always available. What are the potential or actual clinical implications of this work? This study will enable service providers to better plan, justify funding for and delivery of SLT that will meet the needs of PwPPA and their families. Most importantly this work underlines the importance of a person-centred approach, incorporating the broader needs of the person with PPA and those around them.

Reforming support systems of newly diagnosed brain cancer patients: a systematic review.

PURPOSE: Despite the increasing incidence of currently incurable brain cancer, limited resources are placed in patients' support systems, with reactive utilisation late in the disease course, when physical and psychological symptoms have peaked. Based on patient-derived data and emphasis on service improvement, this review investigated the structure and efficacy of the support methods of newly diagnosed brain cancer patients in healthcare systems. METHODS: This systematic review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols. Articles from PubMed, Embase, and CENTRAL databases were screened with six pre-established eligibility criteria, including assessment within 6 months from diagnosis of a primary malignant brain tumour. Risk of bias was evaluated using the Newcastle-Ottawa Scale and Critical Appraisal Skills Program (CASP) Qualitative Studies Checklist. RESULTS: Of 5057 original articles, 14 were eligible for qualitative synthesis. Four studies were cross-sectional and ten were descriptive. Information given to patients was evaluated in seven studies, communication with patients in nine, and patient participation in treatment decisions in eight. Risk of bias was low in ten studies, moderate in two, and high in two. CONCLUSIONS: Techniques promoting individualised care increased perceived support, despite poor patient-physician communication and complexity of the healthcare system. Extracted data across 14 included studies informed a set of guidelines and a four-step framework. These can help evaluate and reform healthcare services to better accommodate the supportive needs of this patient group.

Genetic Study of Early Onset Parkinson's Disease in Cyprus.

Parkinson's Disease (PD) is a multifactorial neurodegenerative disease characterized by motor and non-motor symptoms. The etiology of PD remains unclear. However, several studies have demonstrated the interplay of genetic, epigenetic, and environmental factors in PD. Early-onset PD (EOPD) is a subgroup of PD diagnosed between the ages of 21 and 50. Population genetic studies have demonstrated great genetic variability amongst EOPD patients. Hence, this study aimed to obtain a genetic landscape of EOPD in the Cypriot population. Greek-Cypriot EOPD patients (n = 48) were screened for variants in the six most common EOPD-associated genes (PINK1, PRKN, FBXO7, SNCA, PLA2G6, and DJ-1). This included DNA sequencing and Multiplex ligation-dependent probe amplification (MLPA). One previously described frameshift variant in PINK1 (NM_032409.3:c.889del) was detected in five patients (10.4%)-the largest number to be detected to date. Copy number variations in the PRKN gene were identified in one homozygous and 3 compound heterozygous patients (8.3%). To date, the pathogenic variants identified in this study have explained the PD phenotype for 18.8% of the EOPD cases. The results of this study may contribute to the genetic screening of EOPD in Cyprus.

Performance evaluation of pipelines for mapping, variant calling and interval padding, for the analysis of NGS germline panels.

BACKGROUND: Next-generation sequencing (NGS) represents a significant advancement in clinical genetics. However, its use creates several technical, data interpretation and management challenges. It is essential to follow a consistent data analysis pipeline to achieve the highest possible accuracy and avoid false variant calls. Herein, we aimed to compare the performance of twenty-eight combinations of NGS data analysis pipeline compartments, including short-read mapping (BWA-MEM, Bowtie2, Stampy), variant calling (GATK-HaplotypeCaller, GATK-UnifiedGenotyper, SAMtools) and interval padding (null, 50 bp, 100 bp) methods, along with a commercially available pipeline (BWA Enrichment, Illumina®). Fourteen germline DNA samples from breast cancer patients were sequenced using a targeted NGS panel approach and subjected to data analysis. RESULTS: We highlight that interval padding is required for the accurate detection of intronic variants including spliceogenic pathogenic variants (PVs). In addition, using nearly default parameters, the BWA Enrichment algorithm, failed to detect these spliceogenic PVs and a missense PV in the TP53 gene. We also recommend the BWA-MEM algorithm for sequence alignment, whereas variant calling should be performed using a combination of variant calling algorithms; GATK-HaplotypeCaller and SAMtools for the accurate detection of insertions/deletions and GATK-UnifiedGenotyper for the efficient detection of single nucleotide variant calls. CONCLUSIONS: These findings have important implications towards the identification of clinically actionable variants through panel testing in a clinical laboratory setting, when dedicated bioinformatics personnel might not always be available. The results also reveal the necessity of improving the existing tools and/or at the same time developing new pipelines to generate more reliable and more consistent data.

Implementation of multigene panel NGS diagnosis in the national primary ciliary dyskinesia cohort of Cyprus: An island with a high disease prevalence.

We aimed to determine a genetic diagnosis in the national primary ciliary dyskinesia (PCD) cohort of Cyprus, an island with a high disease prevalence. We used targeted next-generation sequencing (NGS) of 39 PCD genes in 48 patients of Greek-Cypriot and other ancestries. We achieved a molecular diagnosis in 74% of the unrelated families tested. We identified 24 different mutations in 11 genes, 12 of which are novel. Homozygosity was more common in Greek-Cypriot than non-Greek-Cypriot patients (88% vs. 46.2%, p = .016). Four mutations (DNAH11:c.5095-2A>G, CFAP300:c.95_103delGCCGGCTCC, TTC25:c.716G>A, RSPH9:c.670+2T>C) were found in 74% of the diagnosed Greek-Cypriot families. Patients with RSPH9 mutations demonstrated higher nasal nitric oxide (57 vs. 15 nl/min, p <.001), higher forced expiratory volume in 1 s (-0.89 vs. -2.37, p = .018) and forced vital capacity (-1.00 vs. -2.16, p = .029) z scores than the rest of the cohort. Targeted multigene-panel NGS is an efficient tool for early diagnosis of PCD, providing insight into genetic disease epidemiology and improved patient stratification.

The spectrum of BRCA1 and BRCA2 pathogenic sequence variants in Middle Eastern, North African, and South European countries.

BRCA1 BRCA2 mutational spectrum in the Middle East, North Africa, and Southern Europe is not well characterized. The unique history and cultural practices characterizing these regions, often involving consanguinity and inbreeding, plausibly led to the accumulation of population-specific founder pathogenic sequence variants (PSVs). To determine recurring BRCA PSVs in these locales, a search in PUBMED, EMBASE, BIC, and CIMBA was carried out combined with outreach to researchers from the relevant countries for unpublished data. We identified 232 PSVs in BRCA1 and 239 in BRCA2 in 25 of 33 countries surveyed. Common PSVs that were detected in four or more countries were c.5266dup (p.Gln1756Profs), c.181T>G (p.Cys61Gly), c.68_69del (p.Glu23Valfs), c.5030_5033del (p.Thr1677Ilefs), c.4327C>T (p.Arg1443Ter), c.5251C>T (p.Arg1751Ter), c.1016dup (p.Val340Glyfs), c.3700_3704del (p.Val1234Glnfs), c.4065_4068del (p.Asn1355Lysfs), c.1504_1508del (p.Leu502Alafs), c.843_846del (p.Ser282Tyrfs), c.798_799del (p.Ser267Lysfs), and c.3607C>T (p.Arg1203Ter) in BRCA1 and c.2808_2811del (p.Ala938Profs), c.5722_5723del (p.Leu1908Argfs), c.9097dup (p.Thr3033Asnfs), c.1310_1313del (p. p.Lys437Ilefs), and c.5946del (p.Ser1982Argfs) for BRCA2. Notably, some mutations (e.g., p.Asn257Lysfs (c.771_775del)) were observed in unrelated populations. Thus, seemingly genotyping recurring BRCA PSVs in specific populations may provide first pass BRCA genotyping platform.

Environmental profile of an innovative household biowaste dryer system based on Life Cycle Assessment.

An alternative approach to biowaste management involves the application of an innovative household dryer for the dehydration of biowaste at source, in order to significantly reduce its mass and volume, and subsequently the collection frequency. The main objective of this work is to assess the potential impacts of the system under examination, which involves the household dryer use and kerbside collection of the dehydrated residues (biomass), by conducting a Life Cycle Assessment study. The stages considered in the present study include the following: (a) the construction of the household biowaste dryer; (b) the use of the dryer and the collection of dehydrated residues; (c) the end-of-life treatment of the dryer. The results revealed that emissions coming from kerbside collection account for the vast majority of the total emissions from each category examined, apart from Terrestrial Ecotoxicity, where lignite, heavy fuel oil and diesel combustion during electricity production affect mainly this category. The potential impact in Global Warming over 100 years was estimated to be 8.87 kg CO2 eq / t biowaste. The Human Toxicity Potential was 1.86 kg 1,4-DB eq / t biowaste, Terrestrial Ecotoxicity Potential was 0.027 kg 1,4-DB eq / t biowaste, Freshwater Aquatic Ecotoxicity Potential was 0.0126 kg 1,4-DB eq / t biowaste and Marine Aquatic Ecotoxicity Potential was 521.85 kg 1,4-DB eq / t biowaste. Acidification Potential was estimated at 0.035 kg SO2 eq / t biowaste, while Eutrophication Potential was 0.0065 kg PO4- eq / t biowaste. Finally, Photochemical Oxidation Potential was 0.0014 kg C2H4 eq / t biowaste.

Introduction of the trapezoidal thermodynamic technique method for measuring and mapping the efficiency of waste-to-energy plants: A potential replacement to the R1 formula.

Waste-to-energy plants have the peculiarity of being considered both as energy production and as waste destruction facilities and this distinction is important for legislative reasons. The efficiency of waste-to-energy plants must be objective and consistent, independently if the focus is the production of energy, the destruction of waste or the recovery/upgrade of materials. With the introduction of polygeneration technologies, like gasification, the production of energy and the recovery/upgrade of materials, are interconnected. The existing methodology for assessing the efficiency of waste-to-energy plants is the R1 formula, which does not take into consideration the full spectrum of the operations that take place in waste-to-energy plants. This study introduces a novel methodology for assessing the efficiency of waste-to-energy plants and is defined as the 3T method, which stands for 'trapezoidal thermodynamic technique'. The 3T method is an integrated approach for assessing the efficiency of waste-to-energy plants, which takes into consideration not only the production of energy but also the quality of the products. The value that is returned from the 3T method can be placed in a tertiary diagram and the global efficiency map of waste-to-energy plants can be produced. The application of the 3T method showed that the waste-to-energy plants with high combined heat and power efficiency and high recovery of materials are favoured and these outcomes are in accordance with the cascade principle and with the high cogeneration standards that are set by the EU Energy Efficiency Directive.

The synergistic effect between the Mediterranean diet and GSTP1 or NAT2 SNPs decreases breast cancer risk in Greek-Cypriot women.

PURPOSE: Xenobiotic metabolism is related to the interplay between diet and breast cancer (BC) risk. This involves detoxification enzymes, which are polymorphic and metabolise various dietary metabolites. An important characteristic of this pathway is that chemoprotective micronutrients can act not only as substrates but also as inducers for these enzymes. We investigated whether functional GSTP1 (p.Ile105Val-rs1695), NAT2 (590G>A-rs1799930) SNPs and GSTM1 and GSTT1 deletion polymorphisms could modulate the effect of the Mediterranean diet (MD) on BC risk, in Greek-Cypriot women. METHODS: Genotyping was performed on women from the MASTOS case-control study of BC in Cyprus. A 32-item food-frequency questionnaire was used to obtain dietary intake information. A dietary pattern, which closely resembles the MD (high loadings of vegetables, fruit, legumes and fish), was previously derived with principal component analysis and was used as our dietary variable. RESULTS: GSTT1 null genotype increased BC risk compared with the homozygous non-null GSTT1 genotype (OR 1.21, 95 % CI 1.01-1.45). Increasing adherence to the MD reduced BC risk in women with at least one GSTP1 Ile allele (OR for Ile/Ile = 0.84, 95 % CI 0.74-0.95, for Ile/Val = 0.73, 95 % CI 0.62-0.85) or one NAT2 590G allele (OR for 590 GG = 0.73, 95 % CI 0.63-0.83, for 590 GA = 0.81, 95 % CI 0.70-0.94). p interaction values were not, however, statistically significant. CONCLUSION: The homozygous null GSTT1 genotype could be a risk allele for BC among Greek-Cypriot women. The anticarcinogenic effects of the high adherence to MD against BC risk could also be further enhanced when combined with the wild-type alleles of the detoxification GSTP1 or NAT2 SNPs.

MnSOD and CAT polymorphisms modulate the effect of the Mediterranean diet on breast cancer risk among Greek-Cypriot women.

PURPOSE: Oxidative stress arises due to a cellular imbalance in oxidants and antioxidants and/or due to an altered activity of antioxidant enzymes, caused by SNPs. Oxidative stress increases susceptibility to breast cancer (BC) risk, and we previously showed that the Mediterranean diet (MD), which is rich in antioxidants, reduces BC risk in Greek-Cypriot women. Here, we investigated the effect of MnSOD (p.Val16Ala, rs4880) and CAT (-262C>T, rs1001179) SNPs on the association between the MD and BC risk in the case-control study of BC MASTOS in Cyprus. METHODS: Dietary intake data were obtained using a 32-item food frequency questionnaire, from which a dietary pattern was previously derived, using principal component analysis. This pattern included high loadings of vegetables, fruit, legumes and fish, a combination that closely resembles the MD and was used as our dietary variable. RESULTS: High vegetable intake lowered BC risk in women with at least one MnSOD Val allele (ORHigh vs. Low for Val/Val = 0.56, 95 % CI 0.35-0.88, for Val/Ala = 0.57, 95 % CI 0.39-0.82), or one CAT -262C allele (ORHigh vs. Low for -262CC = 0.66, 95 % CI 0.47-0.92, for -262CT = 0.53, 95 % CI 0.35-0.81). High fish intake conferred a decreased BC risk of CAT -262CC women (ORQ4 vs. Q1 0.66, 95 % CI 0.47-0.92) compared with the CAT -262TT women and low fish intake (ORQ2 vs. Q1 2.79, 95 % CI 1.08-7.17). Additionally, high fish intake reduced BC risk in MnSOD Val/Val women (ORQ4 vs. Q1 0.63, 95 % CI 0.40-0.98). p interaction values were, however, not statistically significant. CONCLUSION: Our results demonstrate that the antioxidative effects of the MD against BC risk may be enhanced by the wild-type alleles of the MnSOD or CAT SNPs among Greek-Cypriot women.

Muddles and puzzles: Metaphor use associated with disease progression in Primary Progressive Aphasia.

Background: Primary Progressive Aphasia describes a language-led dementia and its variants. There is little research exploring the experiences of living with this disease. Metaphor, words that represent something else, have been studied extensively in health-related narratives to gain a more intimate insight into health experiences. Aims: This study explored the metaphors used spontaneously by people with PPA, their care partners (family), and speech and language therapists/pathologists (SLT/Ps) providing support along the continuum of care. Methods & Procedures: This study examined two previously collected data sets comprising naturalistic talk where metaphors were not the specific focus, the first from focus groups conducted with people with PPA and their families and the second from focus groups conducted with SLT/Ps working with people with PPA. Transcribed data were analysed for metaphor use through an iterative narrative approach. Outcomes & Results: In all, 237 examples of metaphorical language were identified in the data, with 14 metaphors from people with PPA, 116 from the families and 106 from SLT/Ps. Different metaphors were used by participants to describe their experiences depending on which variant of PPA they were living with, and people also described their disease differently over time. SLT/Ps also used metaphors, however, their language reflected the structured, professional perspective of delivering speech and language therapy services. Conclusions & Implications: SLT/Ps should listen for and recognise the metaphorical language used by people with PPA and their families to ensure therapeutic alignment, see beyond the PPA to recognise the individual's needs, and provide person-centred and empathic support.

Identification of stage-specific breast markers using quantitative proteomics.

Matched healthy and diseased tissues from breast cancer patients were analyzed by quantitative proteomics. By comparing proteomic profiles of fibroadenoma (benign tumors, three patients), DCIS (noninvasive cancer, three patients), and invasive ductal carcinoma (four patients), we identified protein alterations that correlated with breast cancer progression. Three 8-plex iTRAQ experiments generated an average of 826 protein identifications, of which 402 were common. After excluding those originating from blood, 59 proteins were significantly changed in tumor compared with normal tissues, with the majority associated with invasive carcinomas. Bioinformatics analysis identified relationships between proteins in this subset including roles in redox regulation, lipid transport, protein folding, and proteasomal degradation, with a substantial number increased in expression due to Myc oncogene activation. Three target proteins, cofilin-1 and p23 (increased in invasive carcinoma) and membrane copper amine oxidase 3 (decreased in invasive carcinoma), were subjected to further validation. All three were observed in phenotype-specific breast cancer cell lines, normal (nontransformed) breast cell lines, and primary breast epithelial cells by Western blotting, but only cofilin-1 and p23 were detected by multiple reaction monitoring mass spectrometry analysis. All three proteins were detected by both analytical approaches in matched tissue biopsies emulating the response observed with proteomics analysis. Tissue microarray analysis (361 patients) indicated cofilin-1 staining positively correlating with tumor grade and p23 staining with ER positive status; both therefore merit further investigation as potential biomarkers.

Multi-gene panel testing and association analysis in Cypriot breast cancer cases and controls.

Introduction: It is estimated that around 5% of breast cancer cases carry pathogenic variants in established breast cancer susceptibility genes. However, the underlying prevalence and gene-specific population risk estimates in Cyprus are currently unknown. Methods: We performed sequencing on a population-based case-control study of 990 breast cancer cases and 1094 controls from Cyprus using the BRIDGES sequencing panel. Analyses were conducted separately for protein-truncating and rare missense variants. Results: Protein-truncating variants in established breast cancer susceptibility genes were detected in 3.54% of cases and 0.37% of controls. Protein-truncating variants in BRCA2 and ATM were associated with a high risk of breast cancer, whereas PTVs in BRCA1 and PALB2 were associated with a high risk of estrogen receptor (ER)-negative disease. Among participants with a family history of breast cancer, PTVs in ATM, BRCA2, BRCA1, PALB2 and RAD50 were associated with an increased risk of breast cancer. Furthermore, an additional 19.70% of cases and 17.18% of controls had at least one rare missense variant in established breast cancer susceptibility genes. For BRCA1 and PALB2, rare missense variants were associated with an increased risk of overall and triple-negative breast cancer, respectively. Rare missense variants in BRCA1, ATM, CHEK2 and PALB2 domains, were associated with increased risk of disease subtypes. Conclusion: This study provides population-based prevalence and gene-specific risk estimates for protein-truncating and rare missense variants. These results may have important clinical implications for women who undergo genetic testing and be pivotal for a substantial proportion of breast cancer patients in Cyprus.

Spectrum and Frequency of Germline FANCM Protein-Truncating Variants in 44,803 European Female Breast Cancer Cases.

FANCM germline protein truncating variants (PTVs) are moderate-risk factors for ER-negative breast cancer. We previously described the spectrum of FANCM PTVs in 114 European breast cancer cases. In the present, larger cohort, we report the spectrum and frequency of four common and 62 rare FANCM PTVs found in 274 carriers detected among 44,803 breast cancer cases. We confirmed that p.Gln1701* was the most common PTV in Northern Europe with lower frequencies in Southern Europe. In contrast, p.Gly1906Alafs*12 was the most common PTV in Southern Europe with decreasing frequencies in Central and Northern Europe. We verified that p.Arg658* was prevalent in Central Europe and had highest frequencies in Eastern Europe. We also confirmed that the fourth most common PTV, p.Gln498Thrfs*7, might be a founder variant from Lithuania. Based on the frequency distribution of the carriers of rare PTVs, we showed that the FANCM PTVs spectra in Southwestern and Central Europe were much more heterogeneous than those from Northeastern Europe. These findings will inform the development of more efficient FANCM genetic testing strategies for breast cancer cases from specific European populations.

Exome sequencing identifies breast cancer susceptibility genes and defines the contribution of coding variants to breast cancer risk.

Linkage and candidate gene studies have identified several breast cancer susceptibility genes, but the overall contribution of coding variation to breast cancer is unclear. To evaluate the role of rare coding variants more comprehensively, we performed a meta-analysis across three large whole-exome sequencing datasets, containing 26,368 female cases and 217,673 female controls. Burden tests were performed for protein-truncating and rare missense variants in 15,616 and 18,601 genes, respectively. Associations between protein-truncating variants and breast cancer were identified for the following six genes at exome-wide significance (P < 2.5 × 10-6): the five known susceptibility genes ATM, BRCA1, BRCA2, CHEK2 and PALB2, together with MAP3K1. Associations were also observed for LZTR1, ATR and BARD1 with P < 1 × 10-4. Associations between predicted deleterious rare missense or protein-truncating variants and breast cancer were additionally identified for CDKN2A at exome-wide significance. The overall contribution of coding variants in genes beyond the previously known genes is estimated to be small.

The mediterranean dietary pattern and breast cancer risk in Greek-Cypriot women: a case-control study.

BACKGROUND: Diet has long been suspected to impact on breast cancer risk. In this study we evaluated whether the degree of adherence to a Mediterranean diet pattern modifies breast cancer risk amongst Greek-Cypriot women. METHODS: Subjects included 935 cases and 817 controls, all participating in the MASTOS case-control study in Cyprus. The study was approved by the Cyprus National Bioethics Committee. Information on dietary intakes was collected using an interviewer administered 32-item Food Frequency Questionnaire. Information on demographic, anthropometric, lifestyle, and other confounding factors was also collected. Adherence to the Mediterranean Diet pattern was assessed using two a-priory defined diet scores. In addition, dietary patterns specific to our population were derived using Principal Component Analysis (PCA). Logistic regression models were used to assess the association between the dietary patters and breast cancer risk. RESULTS: There was no association with breast cancer risk for either score, however, higher consumptions of vegetables, fish and olive oil, were independently associated with decreased risk. In addition, the PCA derived component which included vegetables, fruit, fish and legumes was shown to significantly reduce risk of breast cancer (ORs across quartiles of increasing levels of consumption: 0.89 95%CI: 0.65-1.22, 0.64 95%CI: 0.47-0.88, 0.67 95%CI: 0.49-0.92, P trend < 0.0001), even after adjustment for relevant confounders. CONCLUSIONS: Our results suggest that adherence to a diet pattern rich in vegetables, fish, legumes and olive oil may favorably influence the risk of breast cancer. This study is the first investigation of dietary effects on breast cancer risk in Cyprus, a country whose population has traditionally adhered to the Mediterranean diet.

Observational study of health utilities in adult primary ciliary dyskinesia patients: preliminary data on associations with molecular diagnosis, clinical phenotype and HRQOL measures.

Background: Primary ciliary dyskinesia (PCD) is a congenital disorder characterized by chronic respiratory morbidity. To date, there is no information on PCD-specific preference-based quality of life measures such as health utilities (HU). We cross-sectionally assessed HU in adult PCD patients and explored relationships with genotype, phenotype and quality of life (QOL)-PCD scales. Methods: Diagnostic testing was performed according to international guidelines, while participants completed the visual analog scale (VAS), time trade off (TTO), standard gamble (SG), and EuroQol 5 dimensions (EQ5D) HU instruments, as well as the QOL-PCD questionnaire. Hierarchical regression was used to identify the QOL-PCD scales that are most predictive of HU. Results: Among 31 patients, median HU are 0.75 (VAS), 0.86 (EQ5D), 0.91 (TTO) and 0.99 (SG). The underlying genotype is not associated with HU measures. VAS and EQ5D are associated with lung function, while TTO and SG values are not sensitive to any of the examined factors. Among the QOL-PCD scales, physical functioning and lower respiratory symptoms explained much of VAS (R2= 0.419) and EQ5D (R2= 0.538) variability. Conclusions: Our study demonstrates that HU elicitation in PCD is feasible using both direct and indirect methods. Overall, HU scores are relatively high among adult patients, with higher scores observed in SG and TTO, followed by EQ5D and VAS. VAS and EQ5D HU values are sensitive to lung function as well as to QOL-PCD physical functioning and lower respiratory symptom scores.

Distinct Reproductive Risk Profiles for Intrinsic-Like Breast Cancer Subtypes: Pooled Analysis of Population-Based Studies.

BACKGROUND: Reproductive factors have been shown to be differentially associated with risk of estrogen receptor (ER)-positive and ER-negative breast cancer. However, their associations with intrinsic-like subtypes are less clear. METHODS: Analyses included up to 23 353 cases and 71 072 controls pooled from 31 population-based case-control or cohort studies in the Breast Cancer Association Consortium across 16 countries on 4 continents. Polytomous logistic regression was used to estimate the association between reproductive factors and risk of breast cancer by intrinsic-like subtypes (luminal A-like, luminal B-like, luminal B-HER2-like, HER2-enriched-like, and triple-negative breast cancer) and by invasiveness. All statistical tests were 2-sided. RESULTS: Compared with nulliparous women, parous women had a lower risk of luminal A-like, luminal B-like, luminal B-HER2-like, and HER2-enriched-like disease. This association was apparent only after approximately 10 years since last birth and became stronger with increasing time (odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.49 to 0.71; and OR = 0.36, 95% CI = 0.28 to 0.46 for multiparous women with luminal A-like tumors 20 to less than 25 years after last birth and 45 to less than 50 years after last birth, respectively). In contrast, parous women had a higher risk of triple-negative breast cancer right after their last birth (for multiparous women: OR = 3.12, 95% CI = 2.02 to 4.83) that was attenuated with time but persisted for decades (OR = 1.03, 95% CI = 0.79 to 1.34, for multiparous women 25 to less than 30 years after last birth). Older age at first birth (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) and breastfeeding (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) were associated with lower risk of triple-negative breast cancer but not with other disease subtypes. Younger age at menarche was associated with higher risk of all subtypes; older age at menopause was associated with higher risk of luminal A-like but not triple-negative breast cancer. Associations for in situ tumors were similar to luminal A-like. CONCLUSIONS: This large and comprehensive study demonstrates a distinct reproductive risk factor profile for triple-negative breast cancer compared with other subtypes, with implications for the understanding of disease etiology and risk prediction.

Replication of genome-wide discovered breast cancer risk loci in the Cypriot population.

Genome-wide association studies (GWAS) have identified associations with robust statistical support for influencing breast cancer susceptibility. Most GWAS and replications have been conducted in Northern European populations and to a lesser extent in Asians, and Ashkenazi Jews. It is important to evaluate whether these variants confer risk across different populations and also to assess the magnitude of risk conferred. The aim of this study was to evaluate previously GWAS-identified breast cancer risk variants in the Cypriot population. Eleven GWAS-discovered single nucleotide polymorphisms (SNPs) were analyzed for association with breast cancer in 1,109 Cypriot female breast cancer patients and 1,177 healthy female controls. Four of the 11 SNPs evaluated were found to be nominally significantly associated (P < 0.05) with breast cancer risk in the Cypriot population. Based on estimated power, five associations would be expected to be nominally significant. The correlation coefficient of effect sizes (per-allele odds ratio) between the Cypriot population and the original GWAS populations where these SNPs had been discovered was 0.58 (P = 0.064), while allele frequencies were very similar (r = 0.88, P < 0.001). Overall, we show modest concordance for breast cancer GWAS-discovered alleles and their effect sizes in the Cypriot population. The effects sizes of GWAS-discovered SNPs need to be verified separately in different populations.