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Shwachman–Diamond syndrome (SDS) is an inherited bone marrow failure disorder that often presents at infancy. Progress has been made in revealing causal mutated genes (SBDS and others), ribosome defects, and hematopoietic aberrations in SDS. However, the mechanism underlying the hematopoietic failure remained unknown, and treatment options are limited. Herein, we investigated the onset of SDS embryonic hematopoietic impairments. We generated SDS and control human‐derived induced pluripotent stem cells (iPSCs). SDS iPSCs recapitulated the SDS hematological phenotype. Detailed stepwise evaluation of definitive hematopoiesis revealed defects that started at the early emerging hematopoietic progenitor (EHP) stage after mesoderm and hemogenic endothelium were normally induced. Hematopoietic potential of EHPs was markedly reduced, and the introduction of SBDS in SDS iPSCs improved colony formation. Transcriptome analysis revealed reduced expression of ribosome and oxidative phosphorylation‐related genes in undifferentiated and differentiated iPSCs. However, certain pathways (e.g., DNA replication) and genes (e.g., CHCHD2) were exclusively or more severely dysregulated in EHPs compared with earlier and later stages. To our knowledge, this study offers for the first time an insight into the embryonic onset of human hematopoietic defects in an inherited bone marrow failure syndrome and reveals cellular and molecular aberrations at critical stages of hematopoietic development toward EHPs. [ABSTRACT FROM AUTHOR]

User-centered models for the development of digital health interventions are not consistently applied in healthcare settings. This study used a five-phase, user-centered approach to develop HEARTPrep©, a psychosocial intervention delivered via mobile app and telehealth to mothers expecting a baby with congenital heart disease (CHD) to promote maternal, family, and child well-being. Phases of intervention development were: (I) establishing partnerships; (II) creating content; (III) developing prototype and testable intervention; (IV) conducting think-aloud testing; and (V) completing beta testing. Partnerships with parents, clinicians, and design/technology experts were integral throughout the development of HEARTPrep©. Parents of children with CHD also served as participants in Phases II-V, contributing to the creation of content and providing feedback to inform the iterative refinement of HEARTPrep©. These five phases produced a refined digital health intervention with promising feasibility, usability, and acceptability results. This user-centered approach can be used to develop digital health interventions targeting various health outcomes. [ABSTRACT FROM AUTHOR]

UnlabelledBile acids are known to play important roles as detergents in the absorption of hydrophobic nutrients and as signaling molecules in the regulation of metabolism. We tested the novel hypothesis that naturally occurring bile acids interfere with protein-mediated hepatic long chain free fatty acid (LCFA) uptake. To this end, stable cell lines expressing fatty acid transporters as well as primary hepatocytes from mouse and human livers were incubated with primary and secondary bile acids to determine their effects on LCFA uptake rates. We identified ursodeoxycholic acid (UDCA) and deoxycholic acid (DCA) as the two most potent inhibitors of the liver-specific fatty acid transport protein 5 (FATP5). Both UDCA and DCA were able to inhibit LCFA uptake by primary hepatocytes in a FATP5-dependent manner. Subsequently, mice were treated with these secondary bile acids in vivo to assess their ability to inhibit diet-induced hepatic triglyceride accumulation. Administration of DCA in vivo via injection or as part of a high-fat diet significantly inhibited hepatic fatty acid uptake and reduced liver triglycerides by more than 50%.ConclusionThe data demonstrate a novel role for specific bile acids, and the secondary bile acid DCA in particular, in the regulation of hepatic LCFA uptake. The results illuminate a previously unappreciated means by which specific bile acids, such as UDCA and DCA, can impact hepatic triglyceride metabolism and may lead to novel approaches to combat obesity-associated fatty liver disease.

We investigated the effects of differential and nondifferential reinforcers on divided control by compound‐stimulus dimensions. Six pigeons responded in a delayed matching‐to‐sample procedure in which a blue or yellow sample stimulus flashed on/off at a fast or slow rate, and subjects reported its color or alternation frequency. The dimension to report was unsignaled (Phase 1) or signaled (Phase 2). Correct responses were reinforced with a probability of.70, and the probability of reinforcers for errors varied across conditions. Comparison choice depended on reinforcer ratios for correct and incorrect responding; as the frequency of error reinforcers according to a dimension increased, control (measured by log d) by that dimension decreased and control by the other dimension increased. Davison and Nevin's (1999) model described data when the dimension to report was unsignaled, whereas model fits were poorer when it was signaled, perhaps due to carryover between conditions. We are the first to test this quantitative model of divided control with reinforcers for errors and when the dimension to report is signaled; hence, further research is needed to establish the model's generality. We question whether divided stimulus control is dimensional and suggest it may instead reflect joint control by compound stimuli and reinforcer ratios. [ABSTRACT FROM AUTHOR]

Organisms may sometimes behave as if a contingency exists between behavior and consequences, even if this is not actually the case. Killeen (1978) suggested that such superstition occurs because of factors that bias subjects to behave "superstitiously" rather than because of failures of discrimination. We systematically replicated Killeen's experiment and compared contingency discrimination between different consequences. Six pigeons responded in a matching‐to‐sample procedure in which a response‐independent or response‐dependent stimulus change, food delivery, or blackout occurred. The pigeons reported whether the consequence was response dependent or response independent by choosing between two side keys. Discrimination was strongest after stimulus changes, weaker after blackouts, and weakest after food deliveries. These differences persisted even after additional training, suggesting asymmetries that may reflect differences in the disruptive effects of different consequences on remembering and/or behavioral mnemonics. Importantly, the pigeons were not biased to report response‐dependent consequences unless that response was consistent with locational biases; that is, they behaved "superstitiously" when there was a reason to be biased to do so. These findings corroborate Killeen's and demonstrate that behavior may deviate from contingencies not necessarily because subjects cannot discriminate those contingencies but because they are biased to behave otherwise. [ABSTRACT FROM AUTHOR]

Stimulus overselectivity describes strong control by one stimulus element at the expense of other equally relevant elements. Research suggests that control by underselected stimuli emerges following extinction of the overselected stimulus ("revaluation") and the emergence is larger when overselectivity is greater. We compared such revaluation effects with a control compound or condition in two experiments. Human participants chose between compound S+ and S‐ stimuli. Then, to assess control by compound‐stimulus elements, participants chose between individual elements in a testing phase without feedback. The S+ element chosen most often (the overselected element) underwent revaluation, during which choice of that element was extinguished and choice of a novel element reinforced. Thereafter, participants completed a retesting phase. Revaluation reduced choice of the overselected element. Choice of the underselected element decreased for participants with low overselectivity but increased for participants with high overselectivity. This was not the case for a control compound that did not undergo revaluation (Experiments 1 and 2) or in a control condition in which the overselected element continued to be reinforced during revaluation (Experiment 2). These findings suggest that overselectivity levels may modulate revaluation effects, and they also highlight the importance of the contingency change in postrevaluation changes in stimulus control. [ABSTRACT FROM AUTHOR]

Objective: Blunt trauma patients with potential cervical spine injury are traditionally immobilised in rigid collars. Recently, this has been challenged. The present study's objective was comparison of the rate of patient‐oriented adverse events in stable, alert, low‐risk patients with potential cervical spine injuries immobilised in rigid versus soft collars. Methods: Unblinded, prospective quasi‐randomised clinical trial of neurologically intact, adult, blunt trauma patients assessed as having potential cervical spine injury. Patients were randomised to collar type. All other aspects of care were unchanged. Primary outcome was patient‐reported discomfort related to neck immobilisation by collar type. Secondary outcomes included adverse neurological events, agitation and clinically important cervical spine injuries (clinical trial registration number: ACTRN12621000286842). Results: A total of 137 patients were enrolled: 59 patients allocated to a rigid collar and 78 to a soft collar. Most injuries were from a fall <1 m (54%) or a motor vehicle crash (21.9%). Median neck pain score of collar immobilisation was lower in the soft collar group (3.0 [interquartile range 0–6.1] vs 6.0 [interquartile range 3–8.8], P < 0.001). The proportion of patients with clinician‐identified agitation was lower in the soft collar group (5% vs 17%, P = 0.04). There were four clinically important cervical spine injuries (two in each group). All were treated conservatively. There were no adverse neurological events. Conclusions: Use of soft rather than rigid collar immobilisation for low‐risk blunt trauma patients with potential cervical spine injury is significantly less painful for patients and results in less agitation. A larger study is needed to determine the safety of this approach or whether collars are required at all. [ABSTRACT FROM AUTHOR]

Adoption of technology in the financial services industry has been accelerating in recent years. To assess its contribution to financial inclusion, we develop a novel digital financial inclusion index covering 52 emerging market and developing economies. We find that (i) the adoption of digital financial services has been a key driver of financial inclusion; and (ii) there is wide variation across countries and regions, with the greatest progress recorded in Africa and Asia. Given the accelerated adoption of digital payments during the COVID‐19 pandemic, policies are needed to close the digital divide to ensure continued progress in financial inclusion and safeguard trust in financial services. [ABSTRACT FROM AUTHOR]

Inherited defects that abrogate the function of the adenosine deaminase (ADA) enzyme and consequently lead to the accumulation of toxic purine metabolites cause profound lymphopenia and severe combined immune deficiency. Additionally, neutropenia and impaired neutrophil function have been reported among ADA-deficient patients. However, due to the rarity of the disorder, the neutrophil developmental abnormalities and the mechanisms contributing to them have not been characterized. Induced pluripotent stem cells (iPSC) generated from two unrelated ADA-deficient patients and from healthy controls were differentiated through embryoid bodies into neutrophils. ADA deficiency led to a significant reduction in the number of all early multipotent hematopoietic progenitors. At later stages of differentiation, ADA deficiency impeded the formation of granulocyte colonies in methylcellulose cultures, leading to a significant decrease in the number of neutrophils generated from ADA-deficient iPSCs. The viability and apoptosis of ADA-deficient neutrophils isolated from methylcellulose cultures were unaffected, suggesting that the abnormal purine homeostasis in this condition interferes with differentiation or proliferation. Additionally, there was a significant increase in the percentage of hyperlobular ADA-deficient neutrophils, and these neutrophils demonstrated significantly reduced ability to phagocytize fluorescent microspheres. Supplementing iPSCs and methylcellulose cultures with exogenous ADA, which can correct adenosine metabolism, reversed all abnormalities, cementing the critical role of ADA in neutrophil development. Moreover, chemical inhibition of the ribonucleotide reductase (RNR) enzyme, using hydroxyurea or a combination of nicotinamide and trichostatin A in iPSCs from healthy controls, led to abnormal neutrophil differentiation similar to that observed in ADA deficiency, implicating RNR inhibition as a potential mechanism for the neutrophil abnormalities. In conclusion, the findings presented here demonstrate the important role of ADA in the development and function of neutrophils while clarifying the mechanisms responsible for the neutrophil abnormalities in ADA-deficient patients. [ABSTRACT FROM AUTHOR]

The management of clinically node-positive breast cancer after neoadjuvant chemotherapy (NAC) has progressed with the potential to avoid the morbidity of axillary lymph node dissection in patients with complete response to therapy. This study addresses the impact of pretreatment nodal burden and tumor subtype on axillary pathologic complete response (AXpCR) in patients treated with NAC to better inform axillary surgical management. A prospective database was reviewed to identify clinically node-positive patients who underwent NAC followed by axillary lymph node dissection. Patients were stratified in accordance with abnormal nodal burden on pretreatment axillary imaging defined as low (1-2 nodes) or high (≥3 nodes), and biologic subtype defined by hormone receptor (HR+, HR-) and HER2 (human epidermal growth factor receptor 2) status. The primary outcome was AXpCR. AXpCR was 43% in the study population. There was no difference in AXpCR between low and high nodal burden groups (44% versus 42%, P = 0.87). Subtype correlated to AXpCR (P < 0.001) with the highest rate (78%) in the HR−/HER2+ group. Overall, HER2+ patients had a significantly higher AXpCR than HER2- subtypes (66% versus 28% P < 0.001). HR and HER2 status were also predictive of AXpCR when comparing patient, tumor, and treatment variables. Biologic subtype better correlated with rates of AXpCR than nodal burden alone with the highest rates of AXpCR in HER2+ patients. Consideration of tumor biology is more informative than nodal burden when evaluating options for axillary management after NAC. [ABSTRACT FROM AUTHOR]

Objective: Accumulating evidence suggests that the prevalence of eating disorders among Chinese women is a public health concern. Prior studies have drawn linkages between conflicting cultural values, identity confusion, and eating disorder symptomatology, which may be relevant for understanding the rise of eating disorders amidst China's rapid economic and sociocultural transformation. Here, we explore how women's experiences with traditional eating norms and modernizing norms of femininity may shape their food and body attitudes. Method: Chinese young adult women (N = 34; aged 18–22 years) participated in semi‐structured interviews focusing on experiences with norms surrounding eating and ideal feminine appearance, perceived conflict between these norms, and their responses to perceived conflict. Interviews were conducted via email (n = 27) or via Skype (n = 7). Participants were not asked about past or present diagnoses of eating disorders. Analysis of responses was guided by the principles of thematic analysis. Results: Women reported encounters with cultural eating norms and feminine appearance norms, and described factors that motivated continued or discontinued adherence to these norms. Women reported strategies of conflict resolution, which resulted in different emotional and behavioral outcomes including eating disorder symptoms. Discussion: Women's experiences with norms surrounding eating and appearance indicate the centrality of these encounters in the formation of individual and interpersonal values. Our findings suggest the importance for clinicians to assist clients in exploring the meanings behind internalized attitudes toward food and body, and to help clients balance interpersonal and individual needs. [ABSTRACT FROM AUTHOR]

Stimuli that provide information about likely future reinforcers tend to shift behavior, provided a reliable relation between the stimulus and the reinforcer can be discriminated. Stimuli that are apparently more reliable exert greater control over behavior. We asked how the subjective value (measured in terms of preference) of reinforcers associated with stimuli influences stimulus control. Five pigeons worked on a concurrent chains procedure in which half of all trials ended in a smaller reinforcer sooner, and the other half in a larger reinforcer later. In Signaled trials, the color and flash duration on the keys in the initial link signaled the outcome of the trial. In Conflicting probe trials, the color and the flash duration signaled conflicting information about the outcome of the trial. Choice in Signaled trials shifted toward the signaled outcome, but was never exclusive. In Conflicting probe trials, control was divided idiosyncratically between the 2 stimulus dimensions, but still favored the outcome with the higher subjective value. Thus, stimulus control depends not only on the perceived reliability of stimuli, but also on the subjective value of the outcome. [ABSTRACT FROM AUTHOR]

The solvent effects on intramolecular [2+2] photocycloadditions of 2'-hydroxyenones is examined and the regio- and stereochemical results of photochemical cycloadditions of 2'-hydroxyenones are described in protic and aprotic solvents. An intramolecular hydrogen bond between the carbonyl and 2'-hydroxyl group is found to govern the facial selectivity between the two interacting pi-systems under photochemical [2+2] conditions.

Highlights • Control by stimuli signaling future reinforcer availability is often weaker in more certain environments. • We examined whether this was the case when reinforcer availability changed over time. • Across conditions, we varied the certainty of the next-reinforcer location at a particular time. • Stimuli strongly controlled behavior and environmental contingencies exerted weak control. • Control by stimuli and by the environment may depend on global, not local, environmental certainty. Abstract Several studies suggest that the degree of control by reinforcer ratios (environment tracking) and by exteroceptive stimuli that signal future reinforcer availability (signal following) depends on environmental certainty: As reinforcers become more likely at one location, environmental contingencies exert stronger control and exteroceptive stimuli exert weaker control. This research has not yet been extended to environments in which reinforcer availability changes across time, even though such changes are present in most natural environments. Thus, in the present experiment, we examined environment tracking and signal following in a concurrent schedule in which the reinforcer ratio reversed to its reciprocal 30 s after a reinforcer delivery and keylight-color stimuli signaled the likely or definite time or location of the next reinforcer. Across conditions, we manipulated environmental certainty by varying the probability of reinforcer deliveries on the locally richer key. This made the location of future reinforcers at a particular time more or less certain, but did not change the overall reinforcer ratio. Changes in local environmental certainty had little to no effect on environment tracking and signal following; in all conditions, keylight-color stimuli strongly controlled choice and reinforcer ratios exerted weak control. The present findings suggest that the extent of environment tracking and signal following is primarily determined by global, not local, environmental certainty. [ABSTRACT FROM AUTHOR]

Highlights • We studied stimulus generalization of response patterns in a multiple peak procedure. • Two training stimuli differentially signaled an FI 5-s and FI 20-s schedule. • Response-rate patterns to one training stimulus generalized nearly exclusively. • This research provides a strong starting point for future studies of generalization under FI schedules. • A thorough understanding of generalization under FI schedules requires analyzing a range of dependent variables. Abstract Stimulus generalization is typically assessed by analyzing overall response rates. Studies of generalization of response-rate patterns across time are less common, despite the ubiquitous nature of time and the strong temporal control over behavior in the natural world. Thus, we investigated generalization of response-rate patterns across time using a multiple peak procedure in pigeons. The frequency (fast or slow) at which the color of a keylight changed signaled a fixed-interval (FI) 5-s or 20-s schedule, counterbalanced across subjects. In peak trials, the frequency of keylight-color changes was varied. For the fast and slow training stimuli, response rates in peak trials were controlled by the arranged FI schedule value; they increased as the arranged reinforcer time approached, and decreased thereafter. Response-rate patterns to all test stimuli were similar to response-rate patterns to the slow training stimulus for all subjects. Thus, overall, strong generalization from the slow training stimulus to all test stimuli was evident, whereas there was little to no generalization from the fast training stimulus. These findings extend past research examining generalization of temporally controlled response-rate patterns, and provide a useful starting point for future investigations of generalization of fixed-interval responding. A thorough understanding of generalization processes requires analysis of dependent variables other than overall response rates, especially when responding is likely to be temporally controlled. [ABSTRACT FROM AUTHOR]