Concept: Tom DeLay
Background The implantable cardioverter-defibrillator (ICD) is highly effective in reducing mortality among patients at risk for fatal arrhythmias, but inappropriate ICD activations are frequent, with potential adverse effects. Methods We randomly assigned 1500 patients with a primary-prevention indication to receive an ICD with one of three programming configurations. The primary objective was to determine whether programmed high-rate therapy (with a 2.5-second delay before the initiation of therapy at a heart rate of ≥200 beats per minute) or delayed therapy (with a 60-second delay at 170 to 199 beats per minute, a 12-second delay at 200 to 249 beats per minute, and a 2.5-second delay at ≥250 beats per minute) was associated with a decrease in the number of patients with a first occurrence of inappropriate antitachycardia pacing or shocks, as compared with conventional programming (with a 2.5-second delay at 170 to 199 beats per minute and a 1.0-second delay at ≥200 beats per minute). Results During an average follow-up of 1.4 years, high-rate therapy and delayed ICD therapy, as compared with conventional device programming, were associated with reductions in a first occurrence of inappropriate therapy (hazard ratio with high-rate therapy vs. conventional therapy, 0.21; 95% confidence interval [CI], 0.13 to 0.34; P<0.001; hazard ratio with delayed therapy vs. conventional therapy, 0.24; 95% CI, 0.15 to 0.40; P<0.001) and reductions in all-cause mortality (hazard ratio with high-rate therapy vs. conventional therapy, 0.45; 95% CI, 0.24 to 0.85; P=0.01; hazard ratio with delayed therapy vs. conventional therapy, 0.56; 95% CI, 0.30 to 1.02; P=0.06). There were no significant differences in procedure-related adverse events among the three treatment groups. Conclusions Programming of ICD therapies for tachyarrhythmias of 200 beats per minute or higher or with a prolonged delay in therapy at 170 beats per minute or higher, as compared with conventional programming, was associated with reductions in inappropriate therapy and all-cause mortality during long-term follow-up. (Funded by Boston Scientific; MADIT-RIT ClinicalTrials.gov number, NCT00947310 .).
A number of new crops have been developed that address important traits of particular relevance for smallholder farmers in Africa. Scientists, policy makers, and other stakeholders have raised concerns that the approval process for these new crops causes delays that are often scientifically unjustified. This article develops a real option model for the optimal regulation of a risky technology that enhances economic welfare and reduces malnutrition. We consider gradual adoption of the technology and show that delaying approval reduces uncertainty about perceived risks of the technology. Optimal conditions for approval incorporate parameters of the stochastic processes governing the dynamics of risk. The model is applied to three cases of improved crops, which either are, or are expected to be, delayed by the regulatory process. The benefits and costs of the crops are presented in a partial equilibrium that considers changes in adoption over time and the foregone benefits caused by a delay in approval under irreversibility and uncertainty. We derive the equilibrium conditions where the net-benefits of the technology equal the costs that would justify a delay. The sooner information about the safety of the technology arrive, the lower the costs for justifying a delay need to be i.e. it pays more to delay. The costs of a delay can be substantial: e.g. a one year delay in approval of the pod-borer resistant cowpea in Nigeria will cost the country about 33 million USD to 46 million USD and between 100 and 3,000 lives.
Delaying gratification is hard, yet predictive of important life outcomes, such as academic achievement and physical health. Prominent theories focus on the role of self-control, hypersensitivity to immediate rewards, and the cost of time spent waiting. However, delaying gratification may also require trust in people delivering future rewards as promised. To test the role of social trust, participants were presented with character vignettes and faces that varied in trustworthiness, and then choose between hypothetical smaller immediate or larger delayed rewards from those characters. Across two experiments, participants were less willing to wait for delayed rewards from less trustworthy characters, and perceived trustworthiness predicted willingness to delay gratification. These findings provide the first demonstration of a causal role for social trust in willingness to delay gratification, independent of other relevant factors, such as self-control or reward history. Thus, delaying gratification requires choosing not only a later reward, but a reward that is potentially less likely to be delivered, when there is doubt about the person promising it. Implications of this work include the need to revise prominent theories of delay of gratification, and new directions for interventions with populations characterized by impulsivity.
Human skin heals more slowly in aged vs. young adults, but the mechanism for this delay is unclear. In humans, eccrine sweat glands (ESGs) and hair follicles underlying wounds generate cohesive keratinocyte outgrowths that expand to form the new epidermis. Here, we compared the re-epithelialization of partial-thickness wounds created on the forearm of healthy young (< 40 yo) and aged (> 70 yo) adults. Our results confirm that the outgrowth of cells from ESGs is a major feature of repair in young skin. Strikingly, in aged skin, although ESG density is unaltered, less than 50% of the ESGs generate epithelial outgrowths during repair (vs. 100% in young). Surprisingly, aging does not alter the wound-induced proliferation response in hair follicles or ESGs. Instead, there is an overall reduced cohesiveness of keratinocytes in aged skin. Reduced cell-cell cohesiveness was most obvious in ESG-derived outgrowths that, when present, were surrounded by unconnected cells in the scab overlaying aged wounds. Reduced cell-cell contact persisted during the repair process, with increased intercellular spacing and reduced number of desmosomes. Together, reduced outgrowths of ESG (i) reduce the initial number of cells participating in epidermal repair, (ii) delay wound closure, and (iii) lead to a thinner repaired epidermis in aged vs. young skin. Failure to form cohesive ESG outgrowths may reflect impaired interactions of keratinocytes with the damaged ECM in aged skin. Our findings provide a framework to better understand the mediators of delayed re-epithelialization in aging and further support the importance of ESGs for the repair of human wounds.
We studied the effects of changes in the milking routine (lack or presence of 30-s prestimulation, 0 or 1, 2 or 4-min delay between preparation and cluster attachment) and environmental perturbation (unusual loud sounds capable of frightening animals just after stall entry or during the course of milking) on milk removal and milking-related behaviour in dairy dromedary camels. A 30-s prestimulation decreased incidence of bimodal milk flow curves and increased occurrence of the best milk ejection patterns with higher milk flow but had limited effect on milk production in our well-trained animals within a good machine milking setting. However, unusual sounds heard from the beginning of milking or even after milk ejection caused inhibition or disruption of milk removal and modification of camels' behaviour. Milk ejection was significantly delayed (1·58±0·17 min), residual milk increased over 40% of total milk yield and average and peak milk flow rates were significantly lowered when unusual noises were heard from the beginning of milking. These environmental perturbations increased signs of vigilance and the number of attempts to escape the milking parlour. Delaying cluster attachment for over 1 min after the end of udder preparation caused serious milk losses. Up to 62% of total milk was withheld in the udder when the delay reached 4 min. Average and peak milk flow rates also decreased significantly with delayed milking. Signs of vigilance and attempts to escape from the milking parlour appeared when camels waited for over 2 min. After a 4-min delay, camels showed signs of acute stress. Defaecation prior to milk ejection (solid faeces) and rumination during milking can be used to assess camels' milk ejection during milking. Animal welfare and milking efficiency can be ensured when camels are pre-stimulated, milked in calm conditions and with cluster attachment within a maximum of a 1-min delay after stimulation.
HIV virions assemble on the plasma membrane and bud out of infected cells using interactions with endosomal sorting complexes required for transport (ESCRTs). HIV protease activation is essential for maturation and infectivity of progeny virions, however, the precise timing of protease activation and its relationship to budding has not been well defined. We show that compromised interactions with ESCRTs result in delayed budding of virions from host cells. Specifically, we show that Gag mutants with compromised interactions with ALIX and Tsg101, two early ESCRT factors, have an average budding delay of ~75 minutes and ~10 hours, respectively. Virions with inactive proteases incorporated the full Gag-Pol and had ~60 minutes delay in budding. We demonstrate that during budding delay, activated proteases release critical HIV enzymes back to host cytosol leading to production of non-infectious progeny virions. To explain the molecular mechanism of the observed budding delay, we modulated the Pol size artificially and show that virion release delays are size-dependent and also show size-dependency in requirements for Tsg101 and ALIX. We highlight the sensitivity of HIV to budding “on-time” and suggest that budding delay is a potent mechanism for inhibition of infectious retroviral release.
Missing consent forms at surgery can lead to delays in patient care, provider frustration, and patient anxiety. We sought to assess the scope and magnitude of this problem at our institution. We surveyed key informants to determine the frequency and effect of missing consent forms. We found that 66% of patients were missing signed consent forms at surgery and that this caused a delay for 14% of operative cases. In many instances, the missing consent forms interfered with team rounds and resident educational activities. In addition, residents spent less time obtaining consent and were often uncomfortable obtaining consent for major procedures. Finally, 40% of faculty felt dissatisfied with resident consent forms, and more than two-thirds felt patients were uncomfortable with being asked for consent by residents. At our center, missing consent forms led to delayed cases, burdensome and inadequate consent by residents, and extra work for nursing staff.
The superiority of hybrids has long been exploited in agriculture, and although many models explaining “heterosis” have been put forth, direct empirical support is limited. Particularly elusive have been cases of heterozygosity for single gene mutations causing heterosis under a genetic model known as overdominance. In tomato (Solanum lycopersicum), plants carrying mutations in SINGLE FLOWER TRUSS (SFT) encoding the flowering hormone florigen are severely delayed in flowering, become extremely large, and produce few flowers and fruits, but when heterozygous, yields are dramatically increased. Curiously, this overdominance is evident only in the background of “determinate” plants, in which the continuous production of side shoots and inflorescences gradually halts due to a defect in the flowering repressor SELF PRUNING (SP). How sp facilitates sft overdominance is unclear, but is thought to relate to the opposing functions these genes have on flowering time and shoot architecture. We show that sft mutant heterozygosity (sft/+) causes weak semi-dominant delays in flowering of both primary and side shoots. Using transcriptome sequencing of shoot meristems, we demonstrate that this delay begins before seedling meristems become reproductive, followed by delays in subsequent side shoot meristems that, in turn, postpone the arrest of shoot and inflorescence production. Reducing SFT levels in sp plants by artificial microRNAs recapitulates the dose-dependent modification of shoot and inflorescence production of sft/+ heterozygotes, confirming that fine-tuning levels of functional SFT transcripts provides a foundation for higher yields. Finally, we show that although flowering delays by florigen mutant heterozygosity are conserved in Arabidopsis, increased yield is not, likely because cyclical flowering is absent. We suggest sft heterozygosity triggers a yield improvement by optimizing plant architecture via its dosage response in the florigen pathway. Exploiting dosage sensitivity of florigen and its family members therefore provides a path to enhance productivity in other crops, but species-specific tuning will be required.
Leprosy is a leading cause of preventable disability worldwide. Delay in diagnosis of patients augments the transmission of infection, and allows progression of disease and more severe disability. Delays in diagnosis greater than ten years have been reported in Brazil. To reduce this delay, it is important to identify factors that hinder patients from presenting to doctors, and those that delay doctors from diagnosing patients once they have presented. This study aimed to explore factors associated with the delayed diagnosis of leprosy in Brazil.
Here, we report three attempts to replicate a finding from an influential psychological study (Griskevicius et al., 2011b). The original study found interactions between childhood SES and experimental mortality-priming condition in predicting risk acceptance and delay discounting outcomes. The original study used US student samples. We used British university students (replication 1) and British online samples (replications 2 and 3) with a modified version of the original priming material, which was tailored to make it more credible to a British audience. We did not replicate the interaction between childhood SES and mortality-priming condition in any of our three experiments. The only consistent trend of note was an interaction between sex and priming condition for delay discounting. We note that psychological priming effects are considered fragile and often fail to replicate. Our failure to replicate the original finding could be due to demographic differences in study participants, alterations made to the prime, or other study limitations. However, it is also possible that the previously reported interaction is not a robust or generalizable finding.