Constraints on Generality (COG) Simons, Daniel J.; Shoda, Yuichi; Lindsay, D. Stephen
Perspectives on psychological science,
11/2017, Letnik:
12, Številka:
6
Journal Article
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Psychological scientists draw inferences about populations based on samples—of people, situations, and stimuli—from those populations. Yet, few papers identify their target populations, and even ...fewer justify how or why the tested samples are representative of broader populations. A cumulative science depends on accurately characterizing the generality of findings, but current publishing standards do not require authors to constrain their inferences, leaving readers to assume the broadest possible generalizations. We propose that the discussion section of all primary research articles specify Constraints on Generality (i.e., a “COG” statement) that identify and justify target populations for the reported findings. Explicitly defining the target populations will help other researchers to sample from the same populations when conducting a direct replication, and it could encourage follow-up studies that test the boundary conditions of the original finding. Universal adoption of COG statements would change publishing incentives to favor a more cumulative science.
Recurrent somatic ASXL1 mutations occur in patients with myelodysplastic syndrome, myeloproliferative neoplasms, and acute myeloid leukemia, and are associated with adverse outcome. Despite the ...genetic and clinical data implicating ASXL1 mutations in myeloid malignancies, the mechanisms of transformation by ASXL1 mutations are not understood. Here, we identify that ASXL1 mutations result in loss of polycomb repressive complex 2 (PRC2)-mediated histone H3 lysine 27 (H3K27) tri-methylation. Through integration of microarray data with genome-wide histone modification ChIP-Seq data, we identify targets of ASXL1 repression, including the posterior HOXA cluster that is known to contribute to myeloid transformation. We demonstrate that ASXL1 associates with the PRC2, and that loss of ASXL1 in vivo collaborates with NRASG12D to promote myeloid leukemogenesis.
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► ASXL1 mutations are loss-of-function mutations ► ASXL1 loss results in a genome-wide reduction in H3K27me3 occupancy ► ASXL1 interacts with the PRC2 complex and is important for PRC2 recruitment ► ASXL1 collaborates with co-occurring oncogenes in vivo to promote leukemogenesis
IMPORTANCE Survivors of critical illness demonstrate skeletal muscle wasting with associated functional
impairment. OBJECTIVE To perform a comprehensive prospective characterization of skeletal ...muscle wasting, defining the
pathogenic roles of altered protein synthesis and breakdown. DESIGN, SETTING, AND PARTICIPANTS Sixty-three critically ill patients (59% male; mean age: 54.7 years 95% CI, 50.0-59.6 years)
with an Acute Physiology and Chronic Health Evaluation II score of 23.5 (95% CI, 21.9-25.2) were
prospectively recruited within 24 hours following intensive care unit (ICU) admission from August
2009 to April 2011 at a university teaching and a community hospital in England. Patients were
recruited if older than 18 years and were anticipated to be intubated for longer than 48 hours, to
spend more than 7 days in critical care, and to survive ICU stay. MAIN OUTCOMES AND MEASURES Muscle loss was determined through serial ultrasound measurement of the rectus femoris
cross-sectional area (CSA) on days 1, 3, 7, and 10. In a subset of patients, the fiber CSA area was
quantified along with the ratio of protein to DNA on days 1 and 7. Histopathological analysis was
performed. In addition, muscle protein synthesis, breakdown rates, and respective signaling pathways
were characterized. RESULTS There were significant reductions in the rectus femoris CSA observed at day 10 (−17.7% 95%
CI, −25.9% to 8.1%; P < .001). In the 28 patients assessed by
all 3 measurement methods on days 1 and 7, the rectus femoris CSA decreased by 10.3% (95% CI, 6.1%
to 14.5%), the fiber CSA by 17.5% (95% CI, 5.8% to 29.3%), and the ratio of protein to DNA by 29.5%
(95% CI, 13.4% to 45.6%). Decrease in the rectus femoris CSA was greater in patients who experienced
multiorgan failure by day 7 (−15.7%; 95% CI, −27.7% to 11.4%) compared with single organ
failure (−3.0%; 95% CI, −5.3% to 2.1%) (P < .001), even
by day 3 (−8.7% 95% CI, −59.3% to 50.6% vs −1.8% 95% CI, −12.3% to
10.5%, respectively; P = .03). Myofiber necrosis occurred in 20 of 37
patients (54.1%). Protein synthesis measured by the muscle protein fractional synthetic rate was
depressed in patients on day 1 (0.035%/hour; 95% CI, 0.023% to 0.047%/hour) compared with rates
observed in fasted healthy controls (0.039%/hour; 95% CI, 0.029% to 0.048%/hour)
(P = .57) and increased by day 7 (0.076% 95% CI, 0.032%-0.120%/hour;
P = .03) to rates associated with fed controls (0.065%/hour 95% CI,
0.049% to 0.080%/hour; P = .30), independent of nutritional load. Leg
protein breakdown remained elevated throughout the study (8.5 95% CI, 4.7 to 12.3 to 10.6 95% CI,
6.8 to 14.4 μmol of phenylalanine/min/ideal body weight × 100;
P = .40). The pattern of intracellular signaling supported increased
breakdown (n = 9, r = −0.83,
P = .005) and decreased synthesis (n = 9,
r = −0.69, P = .04). CONCLUSIONS AND RELEVANCE Among these critically ill patients, muscle wasting occurred early and rapidly during the first
week of critical illness and was more severe among those with multiorgan failure compared with
single organ failure. These findings may provide insights into skeletal muscle wasting in critical
illness.
To update recommendations of the ASCO systemic therapy for hormone receptor (HR)-positive metastatic breast cancer (MBC) guideline.
An Expert Panel conducted a systematic review to identify new, ...potentially practice-changing data.
Fifty-one articles met eligibility criteria and form the evidentiary basis for the recommendations.
Alpelisib in combination with endocrine therapy (ET) should be offered to postmenopausal patients, and to male patients, with HR-positive, human epidermal growth factor receptor 2 (HER2)-negative,
-mutated, ABC, or MBC following prior endocrine therapy with or without a cyclin-dependent kinase (CDK) 4/6 inhibitor. Clinicians should use next-generation sequencing in tumor tissue or cell-free DNA in plasma to detect
mutations. If no mutation is found in cell-free DNA, testing in tumor tissue, if available, should be used as this will detect a small number of additional patients with
mutations. There are insufficient data at present to recommend routine testing for
mutations to guide therapy for HR-positive, HER2-negative MBC. For
or
mutation carriers with metastatic HER2-negative breast cancer, olaparib or talazoparib should be offered in the 1st-line through 3rd-line setting. A nonsteroidal aromatase inhibitor (AI) and a CDK4/6 inhibitor should be offered to postmenopausal women with treatment-naïve HR-positive MBC. Fulvestrant and a CDK4/6 inhibitor should be offered to patients with progressive disease during treatment with AIs (or who develop a recurrence within 1 year of adjuvant AI therapy) with or without one line of prior chemotherapy for metastatic disease, or as first-line therapy. Treatment should be limited to those without prior exposure to CDK4/6 inhibitors in the metastatic setting.Additional information can be found at www.asco.org/breast-cancer-guidelines.
Nausea is a discomforting sensation of gut malaise that remains a major clinical challenge. Several visceral poisons induce nausea through the area postrema, a sensory circumventricular organ that ...detects bloodborne factors. Here, we use genetic approaches based on an area postrema cell atlas to reveal inhibitory neurons that counteract nausea-associated poison responses. The gut hormone glucose insulinotropic peptide (GIP) activates area postrema inhibitory neurons that project locally and elicit inhibitory currents in nausea-promoting excitatory neurons through γ-aminobutyric acid (GABA) receptors. Moreover, GIP blocks behavioral responses to poisons in wild-type mice, with protection eliminated by targeted area postrema neuron ablation. These findings provide insights into the basic organization of nausea-associated brainstem circuits and reveal that area postrema inhibitory neurons are an effective pharmacological target for nausea intervention.
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•A transcriptome-defined area postrema inhibitory neuron type expresses GIPR•GIPR neurons project locally and selectively inhibit nausea-related GFRAL neurons•GIP activates inhibitory neurons, blocks GFRAL neurons, and suppresses nausea•Ablating brainstem GIPR neurons removes anti-nausea effects of GIP
Nausea is an unpleasant sensation of visceral malaise that remains poorly understood at a molecular and cellular level. Zhang et al. uncover brainstem inhibitory neurons that suppress nausea-related behaviors through selective blockade of nausea-promoting, GDF15 responsive-excitatory neurons. Nausea-suppressing neurons can be pharmacologically engaged by the gut hormone glucose insulinotropic peptide (GIP).
Summary
The world would be a better place if there were more people like Alan. What an extraordinary convergence of kindness, reflectiveness, persistence, ethics, breadth of knowledge, and raw ...smarts! He positively and substantially contributed to cognitive, clinical, and social psychology, and to the lives of his students and collaborators. This collection carries that legacy forward. Alan would have relished reading every one of these articles. I am honored by the opportunity to comment. I hope to do so in a way that Alan would approve. I begin with a brief reflection on one of the “big picture” ideas in Alan's work. Then I discuss several issues that I know were near and dear to Alan and that have also occupied my own thinking for years. In addition to scientific accounts of true and false beliefs and memories, my comments are informed by the methodological reform movement. As an oldster, I also take this opportunity to mention a few earlier issues/findings that relate to current controversies.
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