DNA double-strand breaks (DSBs) are potentially lethal lesions that arise spontaneously during normal cellular metabolism, as a consequence of environmental genotoxins or radiation, or during ...programmed recombination processes. Repair of DSBs by homologous recombination generally occurs by gene conversion resulting from transfer of information from an intact donor duplex to both ends of the break site of the broken chromosome. In mitotic cells, gene conversion is rarely associated with reciprocal exchange and thus limits loss of heterozygosity for markers downstream of the site of repair and restricts potentially deleterious chromosome rearrangements. DSBs that arise by replication fork collapse or by erosion of uncapped telomeres have only one free end and are thought to repair by strand invasion into a homologous duplex DNA followed by replication to the chromosome end (break-induced replication, BIR). BIR from one of the two ends of a DSB would result in loss of heterozygosity, suggesting that BIR is suppressed when DSBs have two ends so that repair occurs by the more conservative gene conversion mechanism. Here we show that BIR can occur by several rounds of strand invasion, DNA synthesis and dissociation. We further show that chromosome rearrangements can occur during BIR if dissociation and reinvasion occur within dispersed repeated sequences. This dynamic process could function to promote gene conversion by capture of the displaced invading strand at two-ended DSBs to prevent BIR.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Psoriasis and atopic eczema are common inflammatory skin diseases. Existing research has identified increased risks of common mental disorders (anxiety, depression) in people with eczema and ...psoriasis; however, explanations for the associations remain unclear. We aimed to establish the risk factors for mental illness in those with eczema or psoriasis and identify the population groups most at risk.
We used routinely collected data from the UK Clinical Practice Research Datalink (CPRD) GOLD. Adults registered with a general practice in CPRD (1997-2019) were eligible for inclusion. Individuals with eczema/psoriasis were matched (age, sex, practice) to up to five adults without eczema/psoriasis. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for hazards of anxiety or depression in people with eczema/psoriasis compared to people without. We adjusted for known confounders (deprivation, asthma eczema, psoriatic arthritis psoriasis, Charlson comorbidity index, calendar period) and potential mediators (harmful alcohol use, body mass index BMI, smoking status, and, in eczema only, sleep quality insomnia diagnoses, specific sleep problem medications and high-dose oral glucocorticoids).
We identified two cohorts with and without eczema (1,032,782, matched to 4,990,125 without), and with and without psoriasis (366,884, matched to 1,834,330 without). Sleep quality was imbalanced in the eczema cohorts, twice as many people with eczema had evidence of poor sleep at baseline than those without eczema, including over 20% of those with severe eczema. After adjusting for potential confounders and mediators, eczema and psoriasis were associated with anxiety (adjusted HR 95% CI: eczema 1.14 1.13-1.16, psoriasis 1.17 1.15-1.19) and depression (adjusted HR 95% CI: eczema 1.11 1.1-1.12, psoriasis 1.21 1.19-1.22). However, we found evidence that these increased hazards are unlikely to be constant over time and were especially high 1-year after study entry.
Atopic eczema and psoriasis are associated with increased incidence of anxiety and depression in adults. These associations may be mediated through known modifiable risk factors, especially sleep quality in people with eczema. Our findings highlight potential opportunities for the prevention of anxiety and depression in people with eczema/psoriasis through treatment of modifiable risk factors and enhanced eczema/psoriasis management.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The rapidly evolving digital environment of the social media era has increased the reach of both quality health information and misinformation. Platforms such as YouTube enable easy sharing of ...attractive, if not always evidence-based, videos with large personal networks and the public. Although much research has focused on characterizing health misinformation on the internet, it has not sufficiently focused on describing and measuring individuals' information competencies that build resilience.
This study aims to assess individuals' willingness to share a non-evidence-based YouTube video about strengthening the immune system; to describe types of evidence that individuals view as supportive of the claim by the video; and to relate information-sharing behavior to several information competencies, namely, information literacy, science literacy, knowledge of the immune system, interpersonal trust, and trust in health authority.
A web-based survey methodology with 150 individuals across the United States was used. Participants were asked to watch a YouTube excerpt from a morning TV show featuring a wellness pharmacy representative promoting an immunity-boosting dietary supplement produced by his company; answer questions about the video and report whether they would share it with a cousin who was frequently sick; and complete instruments pertaining to the information competencies outlined in the objectives.
Most participants (105/150, 70%) said that they would share the video with their cousins. Their confidence in the supplement would be further boosted by a friend's recommendations, positive reviews on a crowdsourcing website, and statements of uncited effectiveness studies on the producer's website. Although all information literacy competencies analyzed in this study had a statistically significant relationship with the outcome, each competency was also highly correlated with the others. Information literacy and interpersonal trust independently predicted the largest amount of variance in the intention to share the video (17% and 16%, respectively). Interpersonal trust was negatively related to the willingness to share the video. Science literacy explained 7% of the variance.
People are vulnerable to web-based misinformation and are likely to propagate it on the internet. Information literacy and science literacy are associated with less vulnerability to misinformation and a lower propensity to spread it. Of the two, information literacy holds a greater promise as an intervention target. Understanding the role of different kinds of trust in information sharing merits further research.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Psoriasis biologics: a new era of choice Mahil, Satveer K; Smith, Catherine H
The Lancet (British edition),
09/2019, Letnik:
394, Številka:
10201
Journal Article
Recenzirano
Blockade of IL-23 might cause a more durable, albeit slower, response since it places brakes on this self-amplifying inflammatory cascade at a more upstream point.7 The relative contribution of ...differential drug exposure will be uncovered in future analyses of concentrations of secukinumab and guselkumab in the serum. Biologic drugs offering superior longevity of response thus promise greater benefits for patients. Since the high costs of drug acquisition continue to limit use to those with more severe, recalcitrant psoriasis, a future challenge will be to secure wider and earlier access to these life-changing treatments. CHS is principal investigator on a Medical Research Council-funded consortium (PSORT) in psoriasis, whose industry partners include AbbVie, Sanquin, Qiagen, Pfizer, Novartis, MedImmune, Janssen, and Celgene, and on an Innovative Medicines Initiative-funded academia–industry consortium (BIOMAP) aimed at identifying biomarkers in psoriasis and atopic dermatitis, whose industry partners include Sanofi, LEO Pharma, Boehringer Ingelheim, Pfizer, and UCB Pharma.
Background and Objective
Gilteritinib is a novel, highly selective tyrosine kinase inhibitor approved in the USA, Canada, Europe, Brazil, Korea, and Japan for the treatment of
FLT3
mutation-positive ...acute myeloid leukemia. This article describes the clinical pharmacokinetic profile of gilteritinib.
Methods
The pharmacokinetic profile of gilteritinib was assessed from five clinical studies.
Results
Dose-proportional pharmacokinetics was observed following once-daily gilteritinib administration (dose range 20–450 mg). Median maximum concentration was reached 2–6 h following single and repeat dosing of gilteritinib; mean elimination half-life was 113 h. Elimination was primarily via feces. Exposure to gilteritinib was comparable under fasted and fed conditions. Gilteritinib is primarily metabolized via cytochrome P450 (CYP) 3A4; coadministration of gilteritinib with itraconazole (a strong P-glycoprotein inhibitor and CYP3A4 inhibitor) or rifampicin (a strong P-glycoprotein inducer and CYP3A inducer) significantly affected the gilteritinib pharmacokinetic profile. No clinically relevant interactions were observed when gilteritinib was coadministered with midazolam (a CYP3A4 substrate) or cephalexin (a multidrug and toxin extrusion 1 substrate). Unbound gilteritinib exposure was similar between subjects with hepatic impairment and normal hepatic function.
Conclusions
Gilteritinib exhibits a dose-proportional pharmacokinetic profile in healthy subjects and in patients with relapsed/refractory acute myeloid leukemia. Gilteritinib exposure is not significantly affected by food. Moderate-to-strong CYP3A inhibitors demonstrated a significant effect on gilteritinib exposure. Coadministration of gilteritinib with CYP3A4 or multidrug and toxin extrusion 1 substrates did not impact substrate concentrations. Unbound gilteritinib was comparable between subjects with hepatic impairment and normal hepatic function; dose adjustment is not warranted for patients with hepatic impairment.
Clinical Trial Registration
NCT02014558, NCT02456883, NCT02571816.
Healthcare workers have emerged as a vulnerable population group during COVID-19, and securing supply chains of personal protective equipment (PPE) has been identified as a critical issue to protect ...healthcare workers and to prevent health system overwhelm. While securing PPE is a complex logistical challenge facing many countries, it is vital to recognise the social and health systems issues that structure the differential degrees of risk faced by various subgroups of healthcare workers. As an illustrative case study, the author identifies two key social factors that are likely to face the degrees of risk faced by midwives in the Special Region of Yogyakarta, Indonesia, if and when COVID-19 takes hold in Indonesia. Healthcare workers in both high and low resource-settings globally are likely to face particular risks and vulnerabilities that are shaped by localized social and health systems factors. Qualitative social and health systems research can and should be utilized proactively in order to protect healthcare workers, to inform more equitable program design, and to create a foundation for health equity within the future of global health that emerges from the pandemic.
Gilteritinib is a potent and selective
kinase inhibitor with single-agent clinical efficacy in relapsed/refractory
-mutated acute myeloid leukemia (AML). In this context, however, gilteritinib is not ...curative, and response duration is limited by the development of secondary resistance. To evaluate resistance mechanisms, we analyzed baseline and progression samples from patients treated on clinical trials of gilteritinib. Targeted next-generation sequencing at the time of AML progression on gilteritinib identified treatment-emergent mutations that activate RAS/MAPK pathway signaling, most commonly in
or
Less frequently, secondary
-F691L gatekeeper mutations or
fusions were identified at progression. Single-cell targeted DNA sequencing revealed diverse patterns of clonal selection and evolution in response to FLT3 inhibition, including the emergence of
mutations in
-mutated subclones, the expansion of alternative wild-type
subclones, or both patterns simultaneously. These data illustrate dynamic and complex changes in clonal architecture underlying response and resistance to mutation-selective tyrosine kinase inhibitor therapy in AML. SIGNIFICANCE: Comprehensive serial genotyping of AML specimens from patients treated with the selective FLT3 inhibitor gilteritinib demonstrates that complex, heterogeneous patterns of clonal selection and evolution mediate clinical resistance to tyrosine kinase inhibition in
-mutated AML. Our data support the development of combinatorial targeted therapeutic approaches for advanced AML.
.
.
Homologous recombination (HR) is considered to be an error-free mechanism for the repair of DNA double-strand breaks (DSBs). Indeed, most DSB repair events occur by a non-crossover mechanism limiting ...loss of heterozygosity (LOH) for markers downstream of the site of repair and preventing chromosome rearrangements. However, DSBs that arise by replication fork collapse or by erosion of uncapped telomeres have only one free end and are thought to repair by strand invasion into a homologous duplex DNA followed by replication to the chromosome end (break-induced replication, BIR). As BIR from one of the two ends of a DSB would result in a long tract of LOH it suggests BIR is suppressed when DSBs have two ends in order for repair to occur by a more conservative HR mechanism. Recent studies showed that BIR can occur by several rounds of strand invasion, DNA synthesis and dissociation resulting in chromosome rearrangements when dissociation and reinvasion occur within dispersed repeated sequences. Thus template switching BIR can be highly mutagenic and this process could be important for genome evolution and disease development in humans.
CONTEXT Clinical guidelines for breast cancer survivors without lymphedema advise against upper body exercise, preventing them from obtaining established health benefits of weight lifting. OBJECTIVE ...To evaluate lymphedema onset after a 1-year weight lifting intervention vs no exercise (control) among survivors at risk for breast cancer–related lymphedema (BCRL). DESIGN, SETTING, AND PARTICIPANTS A randomized controlled equivalence trial (Physical Activity and Lymphedema trial) in the Philadelphia metropolitan area of 154 breast cancer survivors 1 to 5 years postunilateral breast cancer, with at least 2 lymph nodes removed and without clinical signs of BCRL at study entry. Participants were recruited between October 1, 2005, and February 2007, with data collection ending in August 2008. INTERVENTION Weight lifting intervention included a gym membership and 13 weeks of supervised instruction, with the remaining 9 months unsupervised, vs no exercise. MAIN OUTCOME MEASURES Incident BCRL determined by increased arm swelling during 12 months (≥5% increase in interlimb difference). Clinician-defined BCRL onset was also evaluated. Equivalence margin was defined as doubling of lyphedema incidence. RESULTS A total of 134 participants completed follow-up measures at 1 year. The proportion of women who experienced incident BCRL onset was 11% (8 of 72) in the weight lifting intervention group and 17% (13 of 75) in the control group (cumulative incidence difference CID, −6.0%; 95% confidence interval CI, −17.2% to 5.2%; P for equivalence = .04). Among women with 5 or more lymph nodes removed, the proportion who experienced incident BCRL onset was 7% (3 of 45) in the weight lifting intervention group and 22% (11 of 49) in the control group (CID, −15.0%; 95% CI, −18.6% to −11.4%; P for equivalence = .003). Clinician-defined BCRL onset occurred in 1 woman in the weight lifting intervention group and 3 women in the control group (1.5% vs 4.4%, P for equivalence = .12). CONCLUSION In breast cancer survivors at risk for lymphedema, a program of slowly progressive weight lifting compared with no exercise did not result in increased incidence of lymphedema. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00194363Published online December 8, 2010. doi:10.1001/jama.2010.1837
Although modern search systems require minimal skill for meeting simple information needs, most systems provide weak support for gaining advanced skill; hence, the goal of designing systems that ...guide searchers in developing expertise. Essential to developing such systems are a description of expert search behavior and an understanding of how it may be acquired. The present study contributes a detailed analysis of the query behavior of 10 students as they completed assigned exercises during a semester‐long course on expert search. Detailed query logs were coded for three dimensions of query expression: the information structure searched, the type of query term used, and intent of the query with respect to specificity. Patterns of query formulation were found to evidence a progression of instruction, suggesting that the students gained knowledge of fundamental system‐independent constructs that underlie expert search, and that domain‐independent search expertise may be defined as the ability to use these constructs. Implications for system design are addressed.
PDF
