29 research outputs found
EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks
BACKGROUND AND AIMS: Acute hepatic porphyria
comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can
experience acute neurovisceral attacks, debilitating chronic
symptoms, and long-term complications. There is a lack of
multinational, prospective data characterizing the disease and
current treatment practices in severely affected patients.
APPROACH AND RESULTS: EXPLORE is a prospective,
multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic
porphyria who experience recurrent attacks. Eligible patients
had a confirmed acute hepatic porphyria diagnosis and had
experienced â„3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months
before the study, patients reported a median (range) of 6
(0-52) acute attacks, with 52 (46%) patients receiving hemin
prophylaxis. Chronic symptoms were reported by 73 (65%)
patients, with 52 (46%) patients experiencing these daily.
During the study, 98 (88%) patients experienced a total of
483 attacks, 77% of which required treatment at a health
care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic
ÎŽ-aminolevulinic acid synthase 1 messenger ribonucleic acid levels, ÎŽ-aminolevulinic acid, and porphobilinogen compared with
the upper limit of normal in healthy individuals were observed
at baseline and increased further during attacks. Patients had
impaired quality of life and increased health care utilization.
CONCLUSIONS: Patients experienced attacks often requiring treatment in a health care facility and/or with hemin, as
well as chronic symptoms that adversely influenced day-to-day
functioning. In this patient group, the high disease burden
and diminished quality of life highlight the need for novel
therapies. (Hepatology 2020;71:1546-1558)
EXPLORE: A prospective, multinational natural history study of patients with acute hepatic porphyria with recurrent attacks
BACKGROUND AND AIMS: Acute hepatic porphyria
comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can
experience acute neurovisceral attacks, debilitating chronic
symptoms, and long-term complications. There is a lack of
multinational, prospective data characterizing the disease and
current treatment practices in severely affected patients.
APPROACH AND RESULTS: EXPLORE is a prospective,
multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic
porphyria who experience recurrent attacks. Eligible patients
had a confirmed acute hepatic porphyria diagnosis and had
experienced â„3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months
before the study, patients reported a median (range) of 6
(0-52) acute attacks, with 52 (46%) patients receiving hemin
prophylaxis. Chronic symptoms were reported by 73 (65%)
patients, with 52 (46%) patients experiencing these daily.
During the study, 98 (88%) patients experienced a total of
483 attacks, 77% of which required treatment at a health
care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic
ÎŽ-aminolevulinic acid synthase 1 messenger ribonucleic acid levels, ÎŽ-aminolevulinic acid, and porphobilinogen compared with
the upper limit of normal in healthy individuals were observed
at baseline and increased further during attacks. Patients had
impaired quality of life and increased health care utilization.
CONCLUSIONS: Patients experienced attacks often requiring treatment in a health care facility and/or with hemin, as
well as chronic symptoms that adversely influenced day-to-day
functioning. In this patient group, the high disease burden
and diminished quality of life highlight the need for novel
therapies. (Hepatology 2020;71:1546-1558)
Asking the right questions: Scoping studies in the commissioning of research on the organisation and delivery of health services
Scoping studies have been used across a range of disciplines for a wide variety of purposes. However, their value is increasingly limited by a lack of definition and clarity of purpose. The UK's Service Delivery and Organisation Research Programme (SDO) has extensive experience of commissioning and using such studies; twenty four have now been completed
Nucleoside/nucleotide reverse transcriptase inhibitor sparing regimen with once daily integrase inhibitor plus boosted darunavir is non-inferior to standard of care in virologically-suppressed children and adolescents living with HIV â Week 48 results of the randomised SMILE Penta-17-ANRS 152 clinical trial
Bostonia. Volume 21
Founded in 1900, Bostonia magazine is Boston University's main alumni publication, which covers alumni and student life, as well as university activities, events, and programs
Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans
Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have
fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in
25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16
regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of
correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP,
while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in
Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium
(LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region.
Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant
enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the
refined data for existing association signals, we estimate that these loci now explain âŒ38.9% of the familial relative risk of PrCa,
an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of
PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent
signals within the same regio
EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurren
Background and Aims: Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients. Approach and Results: EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced â„3 attacks in the prior 12Â months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6Â months. In the 12Â months before the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a health care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic ÎŽ-aminolevulinic acid synthase 1 messenger ribonucleic acid levels, ÎŽ-aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased health care utilization. Conclusions: Patients experienced attacks often requiring treatment in a health care facility and/or with hemin, as well as chronic symptoms that adversely influenced day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies
An updated view of hypothalamic-vascular-pituitary unit function and plasticity
The discoveries of novel functional adaptations of the hypothalamus and anterior pituitary gland for physiological regulation have transformed our understanding of their interaction. The activity of a small proportion of hypothalamic neurons can control complex hormonal signalling, which is disconnected from a simple stimulus and the subsequent hormone secretion relationship and is dependent on physiological status. The interrelationship of the terminals of hypothalamic neurons and pituitary cells with the vasculature has an important role in determining the pattern of neurohormone exposure. Cells in the pituitary gland form networks with distinct organizational motifs that are related to the duration and pattern of output, and modifications of these networks occur in different physiological states, can persist after cessation of demand and result in enhanced function. Consequently, the hypothalamus and pituitary can no longer be considered as having a simple stratified relationship: with the vasculature they form a tripartite system, which must function in concert for appropriate hypothalamic regulation of physiological processes, such as reproduction. An improved understanding of the mechanisms underlying these regulatory features has implications for current and future therapies that correct defects in hypothalamicâpituitary axes. In addition, recapitulating proper network organization will be an important challenge for regenerative stem cell treatment
Genomic investigations of unexplained acute hepatitis in children
Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children
Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19
IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19.
Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19.
DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 nonâcritically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022).
INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (nâ=â257), ARB (nâ=â248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; nâ=â10), or no RAS inhibitor (control; nâ=â264) for up to 10 days.
MAIN OUTCOMES AND MEASURES The primary outcome was organ supportâfree days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes.
RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ supportâfree days among critically ill patients was 10 (â1 to 16) in the ACE inhibitor group (nâ=â231), 8 (â1 to 17) in the ARB group (nâ=â217), and 12 (0 to 17) in the control group (nâ=â231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ supportâfree days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively).
CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes.
TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570