Patient-reported outcome instruments used in immune-checkpoint inhibitor clinical trials in oncology: a systematic review.

Immune-checkpoint inhibitors (ICI) have shown significant benefits for overall survival across various cancer types. Patient-reported outcomes (PROs) are assessed in clinical trials as a measure of efficacy. However, it remains unclear to what extent current PRO instruments capture symptoms specific to ICI toxicities. We conducted a systematic review to identify the use and content validity of PRO instruments in ICI clinical trials in oncology. Literature was retrieved from PubMed, Embase, PsycINFO, Medline and CINAHL databases. Articles presenting ICI clinical trials' PRO results, clinical trial study protocols, and conference abstracts stating the use of PRO measures were assessed. We evaluated the validity of identified instruments by comparing their symptom-related content with the adverse events reported in each ICI clinical trial. From database inception until January 2020, we identified 191 ICI clinical trials stating the use of PRO measures of which 26 published PRO results. The cancer-specific EORTC QLQ-C30 and the generic EQ-5D questionnaires were the most widely used instruments, often in combination with disease-specific PROs. Instruments used to report PRO symptom-related toxicities covered 45% of the most frequently reported AEs, whereas 23% of AEs were partially covered and 29% were not covered at all. Of non-covered AEs, 59% referred to the dermatologic system. Partially covered AEs related to endocrine and specific types of pain. Despite the high frequency of symptom-related toxicities related to ICI, these events are only partially covered (or not addressed) by current PRO instruments, even when combined. Further research is needed to develop new strategies to tailor PRO instruments to specific ICI toxicities

Response to comment on "Human-specific gain of function in a developmental enhancer"

Duret and Galtier argue that human-specific sequence divergence and gain of function in the HACNS1 enhancer result from deleterious biased gene conversion (BGC) with no contribution from positive selection. We reinforce our previous conclusion by analyzing hypothesized BGC events genomewide and assessing the effect of recombination rates on human-accelerated conserved noncoding sequence ascertainment. We also provide evidence that AT → GC substitution bias can coexist with positive selection

Far-Ultraviolet Dust Albedo Measurements in the Upper Scorpius Cloud Using the SPINR Sounding Rocket Experiment

The Spectrograph for Photometric Imaging with Numeric Reconstruction (SPINR) sounding rocket experiment was launched on 2000 August 4 to record far-ultraviolet (912-1450 A) spectral and spatial information for the giant reflection nebula in the Upper Scorpius region. The data were divided into three arbitrary bandpasses (912-1029 A, 1030-1200 A, and 1235-1450 A) for which stellar and nebular flux levels were derived. These flux measurements were used to constrain a radiative transfer model and to determine the dust albedo for the Upper Scorpius region. The resulting albedos were 0.28+/-0.07 for the 912-1029 A bandpass, 0.33+/-0.07 for the 1030-1200 A bandpass, and 0.77+/-0.13 for the 1235-1450 A bandpass

From Cancer to Diarrhea: The Moving Target of Public Concern about Environmental Health Risks

Public concern about the environment can be unpredictable because it is influenced by numerous factors. Environmental health issues often emerge as important because the public is worried about their health especially when it comes to cancer. Public fear of cancer from environmental exposures is reinforced by many of the US regulations that set pollutant limits based on reducing the risk of cancers rather than other health outcomes. While fear of cancer will never dissipate, recent foodborne outbreaks are contributing to raising public awareness of the health effects from microbes. This paper adds to the dialogue about the challenges of enhancing public understanding of environmental health issues. Internal factors, such as worry, that contribute to public outrage are sometimes more important than external factors such as the media. In addition, relying on the media to inform the public about imminent public health risks may be an ineffective approach to enhancing understanding. In the end, scientists and risk communicators are forced to compete with politicians who are often very effective at manipulating public understanding of risk

Signatures of Primordial non-Gaussianities in the Matter Power-Spectrum and Bispectrum: the Time-RG Approach

We apply the time-renormalization group approach to study the effect of primordial non-Gaussianities in the non-linear evolution of cosmological dark matter density perturbations. This method improves the standard perturbation approach by solving renormalization group-like equations governing the dynamics of gravitational instability. The primordial bispectra constructed from the dark matter density contrast and the velocity fields represent initial conditions for the renormalization group flow. We consider local, equilateral and folded shapes for the initial non-Gaussianity and analyze as well the case in which the non-linear parameter f_{NL} parametrizing the strength of the non-Gaussianity depends on the momenta in Fourier space through a power-law relation, the so-called running non-Gaussianity. For the local model of non-Gaussianity we compare our findings for the power-spectrum with those of recent N-body simulations and find that they accurately fit the N-body data up to wave-numbers k \sim 0.25 h/Mpc at z=0. We also present predictions for the (reduced) matter bispectra for the various shapes of non-Gaussianity.Comment: 27 pages, 12 figures. Results and discussion for a particular case added. One figure and one reference added. Matches with the version accepted for publication in the JCAP

An 11p15 Imprinting Centre Region 2 Deletion in a Family with Beckwith Wiedemann Syndrome Provides Insights into Imprinting Control at CDKN1C

We report a three generation family with Beckwith Wiedemann syndrome (BWS) in whom we have identified a 330 kb deletion within the KCNQ1 locus, encompassing the 11p15.5 Imprinting Centre II (IC2). The deletion arose on the paternal chromosome in the first generation and was only associated with BWS when transmitted maternally to subsequent generations. The deletion on the maternal chromosome was associated with a lower median level of CDKN1C expression in the peripheral blood of affected individuals when compared to a cohort of unaffected controls (p<0.05), however was not significantly different to the expression levels in BWS cases with loss of methylation (LOM) within IC2 (p<0.78). Moreover the individual with a deletion on the paternal chromosome did not show evidence of elevated CDKN1C expression or features of Russell Silver syndrome. These observations support a model invoking the deletion of enhancer elements required for CDKN1C expression lying within or close to the imprinting centre and importantly extend and validate a single observation from an earlier study. Analysis of 94 cases with IC2 loss of methylation revealed that KCNQ1 deletion is a rare cause of loss of maternal methylation, occurring in only 3% of cases, or in 1.5% of BWS overall

Beyond maternal death: improving the quality of maternal care through national studies of ‘near-miss’ maternal morbidity

BACKGROUND: Studies of maternal mortality have been shown to result in important improvements to women’s health. It is now recognised that in countries such as the UK, where maternal deaths are rare, the study of near-miss severe maternal morbidity provides additional information to aid disease prevention, treatment and service provision. OBJECTIVES: To (1) estimate the incidence of specific near-miss morbidities; (2) assess the contribution of existing risk factors to incidence; (3) describe different interventions and their impact on outcomes and costs; (4) identify any groups in which outcomes differ; (5) investigate factors associated with maternal death; (6) compare an external confidential enquiry or a local review approach for investigating quality of care for affected women; and (7) assess the longer-term impacts. METHODS: Mixed quantitative and qualitative methods including primary national observational studies, database analyses, surveys and case studies overseen by a user advisory group. SETTING: Maternity units in all four countries of the UK. PARTICIPANTS: Women with near-miss maternal morbidities, their partners and comparison women without severe morbidity. MAIN OUTCOME MEASURES: The incidence, risk factors, management and outcomes of uterine rupture, placenta accreta, haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome, severe sepsis, amniotic fluid embolism and pregnancy at advanced maternal age (≥ 48 years at completion of pregnancy); factors associated with progression from severe morbidity to death; associations between severe maternal morbidity and ethnicity and socioeconomic status; lessons for care identified by local and external review; economic evaluation of interventions for management of postpartum haemorrhage (PPH); women’s experiences of near-miss maternal morbidity; long-term outcomes; and models of maternity care commissioned through experience-led and standard approaches. RESULTS: Women and their partners reported long-term impacts of near-miss maternal morbidities on their physical and mental health. Older maternal age and caesarean delivery are associated with severe maternal morbidity in both current and future pregnancies. Antibiotic prescription for pregnant or postpartum women with suspected infection does not necessarily prevent progression to severe sepsis, which may be rapidly progressive. Delay in delivery, of up to 48 hours, may be safely undertaken in women with HELLP syndrome in whom there is no fetal compromise. Uterine compression sutures are a cost effective second-line therapy for PPH. Medical comorbidities are associated with a fivefold increase in the odds of maternal death from direct pregnancy complications. External reviews identified more specific clinical messages for care than local reviews. Experience-led commissioning may be used as a way to commission maternity services. LIMITATIONS: This programme used observational studies, some with limited sample size, and the possibility of uncontrolled confounding cannot be excluded. CONCLUSIONS: Implementation of the findings of this research could prevent both future severe pregnancy complications as well as improving the outcome of pregnancy for women. One of the clearest findings relates to the population of women with other medical and mental health problems in pregnancy and their risk of severe morbidity. Further research into models of pre-pregnancy, pregnancy and postnatal care is clearly needed

Facilitators and barriers to hypertension self-management in urban African Americans: perspectives of patients and family members.

INTRODUCTION: We aimed to inform the design of behavioral interventions by identifying patients' and their family members' perceived facilitators and barriers to hypertension self-management. MATERIALS AND METHODS: We conducted focus groups of African American patients with hypertension and their family members to elicit their views about factors influencing patients' hypertension self-management. We recruited African American patients with hypertension (n = 18) and their family members (n = 12) from an urban, community-based clinical practice in Baltimore, Maryland. We conducted four separate 90-minute focus groups among patients with controlled (one group) and uncontrolled (one group) hypertension, as well as their family members (two groups). Trained moderators used open-ended questions to assess participants' perceptions regarding patient, family, clinic, and community-level factors influencing patients' effective hypertension self-management. RESULTS: Patient participants identified several facilitators (including family members' support and positive relationships with doctors) and barriers (including competing health priorities, lack of knowledge about hypertension, and poor access to community resources) that influence their hypertension self-management. Family members also identified several facilitators (including their participation in patients' doctor's visits and discussions with patients' doctors outside of visits) and barriers (including their own limited health knowledge and patients' lack of motivation to sustain hypertension self-management behaviors) that affect their efforts to support patients' hypertension self-management. CONCLUSION: African American patients with hypertension and their family members reported numerous patient, family, clinic, and community-level facilitators and barriers to patients' hypertension self-management. Patients' and their family members' views may help guide efforts to tailor behavioral interventions designed to improve hypertension self-management behaviors and hypertension control in minority populations