Analyzing age-specific genetic effects on human extreme age survival in cohort-based longitudinal studies

The analysis of age-specific genetic effects on human survival over extreme ages is confronted with a deceleration pattern in mortality that deviates from traditional survival models and sparse genetic data available. As human late life is a distinct phase of life history, exploring the genetic effects on extreme age survival can be of special interest to evolutionary biology and health science. We introduce a non-parametric survival analysis approach that combines population survival information with individual genotype data in assessing the genetic effects in cohort-based longitudinal studies. Our approach is characterized by non-parametric analysis of late age survival to capture the observed pattern of mortality deceleration and frailty modeling to account for individual heterogeneity in unobserved frailty. The method is applied to ApoE genotype data in the Danish 1905 birth cohort to estimate effect of the e4 allele. Our results revealed an age-specific relative risk of the allele that increases nonlinearly with age and non-proportional patterns in hazard of death for carriers and non-carriers of the allele, suggesting that the e4 mutation preserves its deleterious effect that progressively affect human survival even at extreme ages.     

Sentinel Lymph Node Dissection in Locally Recurrent Breast Cancer

Annals of Surgical Oncology - The aim of this study was to investigate the use of sentinel lymph node dissection (SLND) in the treatment of patients with locally recurrent breast cancer. A total of...     

Perception of sexuality and fertility in women living with HIV: a questionnaire study from two Nordic countries

Introduction

As the human immunodeficiency virus (HIV)-positive population ages, issues concerning sexuality and fertility, among others, are becoming relevant. HIV is still surrounded by stigma and taboos, and there have been few studies conducted in industrialized settings concerning these questions. We therefore wanted to investigate the perception of sexuality and fertility in women living with HIV (WLWH) in an industrialized setting, using a questionnaire.

Methods

WLWH were recruited at their regular outpatient clinic visits, at the major Departments of Infectious Diseases in Denmark and Finland, from January 2012 to October 2013. A questionnaire was developed, study participants were informed of the nature of study and, if they agreed to participate and signed a consent form, they filled in the questionnaire. Demographic information on the participants was obtained from patient files (in Finland) or from a national HIV cohort (in Denmark). Statistical analysis was performed using STATA^®, version 11.

Results

In total, 560 women were included in the study. The median age was 44 years. The majority were of white European origin, with fully suppressed HIV viral load, CD4 cell count >350 µL and mild or no symptoms of their HIV infection. A total of 62% were sexually active, stating condom use as their sole form of contraception. Of the sexually inactive women, one-third were in steady relationships. Eighty percent reported prior pregnancies, of which the majority had one or more children. Most children were born prior to the women''s HIV diagnosis and the mode of conception was predominantly natural. One-quarter of the participating women desired pregnancy, while more than half did not. The remaining quarter either stated that they already had the desired number of children or chose not to answer the question. Fourteen percent stated that their HIV diagnosis ended their wish for children; of these women, the median time of diagnosis was between 1995 and 1996. Pregnancy had been attempted unsuccessfully in one-quarter of study participants. The final question inquired what the risk of mother-to-child transmission was, with all precautions taken. Fifteen percent estimated the risk to be above two percent.

Conclusions

In conclusion, the majority of WLWH in industrialized settings in Denmark and Finland have few HIV-related symptoms, are sexually active and have a strong desire for children.     

Functional characterization of BRCA1 gene variants by mini-gene splicing assay

Mutational screening of the breast cancer susceptibility gene BRCA1 leads to the identification of numerous pathogenic variants such as frameshift and nonsense variants, as well as large genomic rearrangements. The screening moreover identifies a large number of variants, for example, missense, silent, and intron variants, which are classified as variants of unknown clinical significance owing to the lack of causal evidence. Variants of unknown clinical significance can potentially have an impact on splicing and therefore functional examinations are warranted to classify whether these variants are pathogenic or benign. Here we validate a mini-gene splicing assay by comparing the results of 24 variants with previously published data from RT-PCR analysis on RNA from blood samples/lymphoblastoid cell lines. The analysis showed an overall concordance of 100%. In addition, we investigated 13 BRCA1 variants of unknown clinical significance or putative variants affecting splicing by in silico analysis and mini-gene splicing assay. Both the in silico analysis and mini-gene splicing assay classified six BRCA1 variants as pathogenic (c.80+1G>A, c.132C>T (p.=), c.213−1G>A, c.670+1delG, c.4185+1G>A, and c.5075−1G>C), whereas six BRCA1 variants were classified as neutral (c.-19-22_-19-21dupAT, c.302−15C>G, c.547+14delG, c.4676−20A>G, c.4987−21G>T, and c.5278−14C>G) and one BRCA1 variant remained unclassified (c.670+16G>A). In conclusion, our study emphasizes that in silico analysis and mini-gene splicing assays are important for the classification of variants, especially if no RNA is available from the patient. This knowledge is crucial for proper genetic counseling of patients and their family members.     

Longing for existential recognition: A qualitative study of everyday concerns for people with somatoform disorders

Objective

Patients with somatoform disorders could be vulnerable to stressors and have difficulties coping with stress. The aim was to explore what the patients experience as stressful and how they resolve stress in everyday life.

Methods

A cross-sectional retrospective design using 24 semi-structured individual life history interviews. Data-analysis was based on grounded theory.

Results

A major concern in patients was a longing for existential recognition. This influenced the patients' self-confidence, stress appraisals, symptom perceptions, and coping attitudes. Generally, patients had difficulties with self-confidence and self-recognition of bodily sensations, feelings, vulnerability, and needs, which negatively framed their attempts to obtain recognition in social interactions. Experiences of recognition appeared in three different modalities: 1) “existential misrecognition” covered the experience of being met with distrust and disrespect, 2) “uncertain existential recognition” covered experiences of unclear communication and a perception of not being totally recognized, and 3) “successful existential recognition” covered experiences of total respect and understanding. “Misrecognition” and “uncertain recognition” related to decreased self-confidence, avoidant coping behaviours, increased stress, and symptom appraisal; whereas “successful recognition” related to higher self-confidence, active coping behaviours, decreased stress, and symptom appraisal.

Conclusion

Different modalities of existential recognition influenced self-identity and social identity affecting patients' daily stress and symptom appraisals, self-confidence, self-recognition, and coping attitudes. Clinically it seems crucial to improve the patients' ability to communicate concerns, feelings, and needs in social interactions. Better communicative skills and more active coping could reduce the harm the patients experienced by not being recognized and increase the healing potential of successful recognition.