Exploring patients’ opinions of activity pacing and a new activity pacing questionnaire for chronic pain and/or fatigue:a qualitative study

Objective: Despite the frequent recommendation of activity pacing as a coping strategy for patients with chronic pain and/or fatigue, pacing is interpreted in different ways and there is an absence of a widely accepted pacing scale. We have developed a new Activity Pacing Questionnaire(APQ). The aims of this study were to explore patients’ views and beliefs about the concept of pacing, together with the acceptability of the APQ. Design: Qualitative pragmatic study using semi-structured telephone interviews. Data were analysed using Framework analysis. Participants 16 adult patients attending secondary care physiotherapy out-patient departments were recruited via purposive sampling. Diagnoses included chronic low back pain, chronic widespread pain, fibromyalgia and chronic fatigue syndrome/myalgic encephalomyelitis. Findings: Pacing emerged as a multifaceted concept from participants’ descriptions. The implementation of pacing was influenced by participants’ age, the presence of co-morbidities and participants’ emotions. The APQ was found to be generally acceptable in comparison to two existing pacing subscales. Participants undertook activities using quota/symptom-contingent approaches. Four behavioural typologies emerged: Task avoidance, Task persistence, Task fluctuation (boom-bust) and Task modification (activity pacing). Conclusions: The APQ appears to be easy to complete, and acceptable to patients who are attending physiotherapy for the management of long-term conditions. It emerged that individual patients implemented different pacing facets to varying degrees, and that different behavioural typologies were apparent. The relationships between behavioural typologies and facets of pacing warrant further investigation to facilitate the development of effective tailored pacing interventions

GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5–2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility

Two patients with Hermansky Pudlak syndrome type 2 and novel mutations in AP3B1

Hermansky Pudlak syndrome type 2 (HPS2) is a rare disorder associated with mutations in the Adaptor Protein 3 (AP-3) complex, which is involved in sorting transmembrane proteins to lysosomes and related organelles. We now report 2 unrelated subjects with HPS2 who show a characteristic clinical phenotype of oculocutaneous albinism, platelet and T-lymphocyte dysfunction and neutropenia. The subjects were homozygous for different deletions within AP3B1 (g.del180242-180866, c.del153-156), which encodes the AP-3β3A subunit, resulting in frame shifts and introduction of nonsense substitutions (p.E693fsX13, p.E52fsX11). In the subject with p.E693fsX13, this resulted in expression of a truncated variant β3A protein. Cytotoxic T-lymphocyte (CTL) clones from both study subjects showed increased cell-surface expression of CD63 and reduced cytotoxicity. Platelets showed impaired aggregation and reduced uptake of 3H-serotonin. These findings are consistent with CTL granule and platelet dense granule defects, respectively. This report extends the clinical and laboratory description of HPS2

Myelodysplasia and liver disease extend the spectrum of RTEL1 related telomeropathies.

Regulator of telomere elongation helicase 1 (RTEL1) is a DNA helicase involved in telomere maintenance.1,2 Germline biallelic RTEL1 variants have been previously reported in a subset of patients with dyskeratosis congenita (DC) and its severe variant Hoyeraal-Hreidarsson syndrome (HH).3–6 Furthermore, germline heterozygous RTEL1 variants have been linked to a subset of patients with pulmonary fibrosis.2,7,8 We have undertaken sequencing analysis (whole exome and targeted9) of RTEL1, using genomic DNA extracted from peripheral blood of 429 patients from our international bone marrow failure registry which includes DC, HH, aplastic anemia (AA), and familial myelodysplasia/leukemia (MDS/AML). This has revealed that 35 out of the 429 patients have RTEL1 variants (Table 1). Based on the minor allele frequency in the population reported on the Exome Aggregation Consortium database (ExAC – http://exac.broadinstitute.org/), the type of variant (missense, nonsense and indels), telomere length, the Combined Annotation Depletion (CADD) score,10 and segregation as well as information found in literature, we classified these variants into four different groups: (1) biallelic variants, (2) heterozygous loss of function (LOF) variants, (3) heterozygous missense variants of unknown significance (VUS) and (4) heterozygous missense bystander variants

Acquisition of genome-wide copy number alterations in monozygotic twins with acute lymphoblastic leukemia

Chimaeric fusion genes are highly prevalent in childhood acute lymphoblastic leukaemia (ALL) and are mostly pre-natal, early genetic events in the evolutionary trajectory of this cancer. ETV6-RUNX1-positive ALL also has multiple (~six per case) copy number alterations (CNA) as revealed by genome-wide SNP arrays. Recurrent CNA are probably 'driver' events contributing critically to clonal diversification and selection but, at diagnosis, their developmental timing is 'buried' in the leukaemia's covert natural history. This conundrum can be resolved with twin pairs. We identified and compared CNA in five pairs of monozygotic twins with concordant ETV6-RUNX1-positive ALL and one pair discordant for ETV6-RUNX1 positive ALL. We compared, within each pair, CNA classified as potential 'driver' or 'passenger' mutations based upon recurrency and, where known, gene function. An average of 5.1 (range 3-11) CNAs (excluding immunoglobulin/T-cell receptor alterations) were identified per case. All 'driver' CNA (total 32) were distinct within each of the five twin pairs with concordant ALL. 'Driver' CNA in another twin with ALL were all absent in the shared ETV6-RUNX1-positive pre-leukaemic clone of her healthy co-twin. These data place all 'driver' CNA secondary to the pre-natal gene fusion event and most probably post-natal in the sequential, molecular pathogenesis of ALL

Durable remissions in TCF3-HLF positive acute lymphoblastic leukemia with blinatumomab and stem cell transplantation

WOS: 000469839300005PubMed ID: 30765470TCF3-HLF-positive leukemia represents a rare subtypeof childhood acute lymphoblastic leukemia (ALL), characterized by a high rate of treatment failure despite treatment intensification and allogeneic stem cell transplantation (SCT). Given the high and homogeneous expressionof CD19 on blast cells of this leukemia subtype, thesepatients may benefit from CD19-directed immunotherapy. Here, we report the experience on nineTCF3-HLF-positive ALL patients, most of whom weretreated early in first consolidation with blinatumomab asa bridge to SCT between 2015 and 2018. Treatment withblinatumomab was generally well tolerated; reversibleneurotoxicity was observed in two patients. All ninepatients achieved molecular remission after blinatumomab treatment; seven underwent SCT and for onepatient SCT is planned. Median follow up after start ofblinatumomab treatment was 342 days, and four patientsremain in molecular remission after a follow up of 1317,1292, 1245, and 342 days, respectively. Three patientsdied because of infectious complications not directlyrelated to blinatumomab, because they occurred eitherafter SCT or after emergence of a CD19-negativeleukemia clone. In the light of these encouraging observations, CD19-directed immunotherapy should be considered early after induction chemotherapy inTCF3-HLF-positive ALL children and patients’ outcomemonitored systematically by study groups