Factors associated with self-perceived burden to the primary caregiver in older patients with hematologic malignancies: an exploratory study

Objective: Although cancer patients frequently experience self-perceived burden to others, this perception has not been enough studied. The aim of this study was to investigate the prevalence of selfperceived burden to the primary caregiver (SPB-PC) and associated factors in an older patient population with hematologic malignancies at the time of chemotherapy initiation. Methods: In total, 166 consecutive patients with hematologic malignancies aged ≥65 years were recruited at the time of chemotherapy initiation. Patients’ SPB-PC was assessed using a 100-mm visual analogue scale (VAS). Characteristics potentially associated with SPB-PC, including sociodemographic and medical characteristics, physical functioning status (Karnofsky performance score, activities of daily living (ADL)/instrumental ADL), symptoms (fatigue, pain, nausea, quality of life), psychological distress (Hospital Anxiety and Depression Scale (HADS)), perceived cognitive function (Functional Assessment of Cancer Therapy Cognitive (FACT-Cog) Scale), and patients’/primary caregivers’ personal relationship characteristics (family tie, support), were assessed. Results: Thirty-five percent of patients reported moderate to severe SPB-PC (VAS ≥ 50 mm). Patients’ SPB-PC was associated with lower Karnofsky performance (β = 0.135, p = 0.058) and ADL (β = 0.148, p = 0.037) scores, and higher HADS (β = 0.283, p<0.001) and FACT-Cog perceived cognitive impairments subscale (β = 0.211, p = 0.004) scores. The proportion of explained variance was 23.5%. Conclusions: Health care professionals should be aware that about one third of older cancer patients experience moderate to severe SPB-PC at the time of chemotherapy initiation. They should adapt their support of patients who report such a feeling

High prevalence of PRPH2 in autosomal dominant retinitis pigmentosa in France and characterization of biochemical and clinical features.

International audiencePURPOSE:To assess the prevalence of PRPH2 in autosomal dominant retinitis pigmentosa (adRP), to report six novel mutations, to characterize the biochemical features of a recurrent novel mutation and to study the clinical features of adRP patients.DESIGN:Retrospective clinical and molecular genetic study.METHODS:Clinical investigations included visual field testing, fundus examination, high-resolution spectral-domain optical coherence tomography (OCT), fundus autofluorescence imaging and electroretinogram (ERG) recording. PRPH2 was screened by Sanger sequencing in a cohort of 310 French families with adRP. Peripherin-2 protein was produced in yeast and analyzed by Western blot.RESULTS:We identified 15 mutations, including 6 novel and 9 previously reported changes in 32 families, accounting for a prevalence of 10.3% in this adRP population. We showed that a new recurrent p.Leu254Gln mutation leads to protein aggregation, suggesting abnormal folding. The clinical severity of the disease in examined patients was moderate with 78% of the eyes having 1 to 0.5 of visual acuity and 52% of the eyes retaining more than 50% of the visual field. Some patients characteristically showed vitelliform deposits or macular involvement. In some families, pericentral RP or macular dystrophy were found in family members while widespread RP was present in other members of the same families.CONCLUSIONS:The mutations in PRPH2 account for 10.3% of adRP in the French population, which is higher than previously reported (0-8%) This makes PRPH2 the second most frequent adRP gene after RHO in our series. PRPH2 mutations cause highly variable phenotypes and moderate forms of adRP, including mild cases which could be underdiagnosed

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Applicability and Efficiency of NGS in Routine Diagnosis: In-Depth Performance Analysis of a Complete Workflow for CFTR Mutation Analysis.

BACKGROUND:Actually, about 2000 sequence variations have been documented in the CFTR gene requiring extensive and multi-step genetic testing in the diagnosis of cystic fibrosis and CFTR-related disorders. We present a two phases study, with validation and performance monitoring, of a single experiment methodology based on multiplex PCR and high throughput sequencing that allows detection of all variants, including large rearrangements, affecting the coding regions plus three deep intronic loci. METHODS:A total of 340 samples, including 257 patients and 83 previously characterized control samples, were sequenced in 17 MiSeq runs and analyzed with two bioinformatic pipelines in routine diagnostic conditions. We obtained 100% coverage for all the target regions in every tested sample. RESULTS:We correctly identified all the 87 known variants in the control samples and successfully confirmed the 62 variants identified among the patients without observing false positive results. Large rearrangements were identified in 18/18 control samples. Only 17 patient samples showed false positive signals (6.6%), 12 of which showed a borderline result for a single amplicon. We also demonstrated the ability of the assay to detect allele specific dropout of amplicons when a sequence variation occurs at a primer binding site thus limiting the risk for false negative results. CONCLUSIONS:We described here the first NGS workflow for CFTR routine analysis that demonstrated equivalent diagnostic performances compared to Sanger sequencing and multiplex ligation-dependent probe amplification. This study illustrates the advantages of NGS in term of scalability, workload reduction and cost-effectiveness in combination with an improvement of the overall data quality due to the simultaneous detection of SNVs and large rearrangements

Genotypes tested in validation phase (phase 1).

<p>Genotypes tested in validation phase (phase 1).</p

Depth of coverage analysis for phase 2 samples.

<p>The coverage analysis is based on the number of R1 reads counted for each amplicon with MiSeq Reporter. Values were calculated for the 275 samples tested in phase 2 (CNVs positive controls were excluded). (A) Box plot diagram of the RPC_COV. Box plots show mean (horizontal grey line), 95^th percentile values (box outline) and minimal/maximal values (whiskers). (B) Mean (solid line) and median (dotted line) depth of coverage values by amplicon.</p

Impact of primer trimming on variant calling.

<p>(A) Overestimation of WT allele at variant A locus due to the presence of the primers sequence in the sequencing reads of Amplicon 2 as observed for c.1000C>T (the same principle applies to c.2583del and c.2589_2599del, which are located under the R2 primer of Amplicon 1). When no allele drop-out occurred, variant A is present in 3/12 reads in R1 direction (3/6 from Amplicon1 and 0/6 from Amplicon2) and 3/6 reads in R2 direction for Amplicon1 for a total VAF of 6/18 = 33%. There is a risk of false negative for variant A if the depth of coverage of Amplicon2 is superior to Amplicon1, resulting in a VAF under the detection threshold. In the case of an allele drop-out of Amplicon 2 due to the presence of variant A, then variant A is present in 3/9 reads in R1 direction (3/6 from Amplicon1 and 0/3 from Amplicon2) and 3/6 reads in R2 direction for Amplicon1 for a total VAF of 6/15 = 40%. In this case there is also a risk of false negative if a second variant is associated in cis with variant A (as illustrated by variant B). (B) Impact of primer trimming to limit the risk of false negative results. When primer sequences are removed from the reads, the VAF for variant A is 50% independently of the risk of allele drop-out. In the case of a complex allele involving variant A and B, the risk of false negative result for variant B due to allele drop-out of Amplicon 2 is still present and can be addressed by concomitant CNVs detection followed by Sanger sequencing with a different primer set.</p

Variants identified in the performance monitoring phase (Phase 2).

<p>Variants identified in the performance monitoring phase (Phase 2).</p

CNVs analysis of Phase 2 samples.

<p>RPC_CNV for (1) every amplicon of 3 negative samples verified by MLPA, (2) deleted amplicons for CFTRdele2_3 (n = 14) and CFTRdele1_24 (n = 1) positive controls, (3) apparently deleted amplicons in false positive samples (n = 6 samples for 15 amplicons), (4) duplicated amplicons for CFTRdup4_10 controls (n = 2) and (5) apparently duplicated amplicons in false positive samples (n = 14 samples for 20 amplicons). Three samples showed false positive signals for both deletion and amplification. Dot lines indicate thresholds for deletion (0.7) and duplication (1.3).</p

A mild method for the replacement of a hydroxyl group by halogen. 1, Scope and chemoselectivity

α-Chloro-, bromo- and iodoenamines, which are readily prepared from the corresponding isobutyramides have been found to be excellent reagents for the transformation of a wide variety of alcohols or carboxylic acids into the corresponding halides. Yields are high and conditions are very mild thus allowing for the presence of sensitive functional groups. The reagents can be easily tuned allowing therefore the selective monohalogenation of polyhydroxylated molecules. The scope and chemoselectivity of the reactions have been studied and reaction mechanisms have been proposed