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Moral problems such as climate change and global poverty result from widespread human action, and hence, are unaffected by changes in any individual's behavior—for instance, the harms of climate change will obtain whether I drive my car or not. This problem of causal impotence seems potentially devastating for consequentialists, but more easily addressed by deontologists. The deontologist can argue that (e.g.) even if our acts will have no effect on climate change, our using fossil fuels makes us complicit in, and hence, blameworthy for, these wrongs. We argue that, despite initial appearances, appeals to complicity do not extricate deontologists from this problem. When our actions do not make a difference, we cannot be held responsible for being complicit in wrongs such as climate change and global poverty. As a result, we conclude that the problem of causal impotence is as vexing for deontologists as it is for consequentialists.

Despite the central role of IFN-γ in vitiligo pathogenesis, systemic IFN-γ neutralization is an impractical treatment option owing to strong immunosuppression. However, most patients with vitiligo present with20% affected body surface area, which provides an opportunity for localized treatments that avoid systemic side effects. After identifying keratinocytes as key cells that amplify IFN-γ signaling during vitiligo, we hypothesized that tethering an IFN-γ‒neutralizing antibody to keratinocytes would limit anti‒IFN-γ effects on the treated skin for the localized treatment. To that end, we developed a bispecific antibody capable of blocking IFN-γ signaling while binding to desmoglein expressed by keratinocytes. We characterized the effect of the bispecific antibody in vitro, ex vivo, and in a mouse model of vitiligo. Single-photon emission computed tomography/computed tomography biodistribution and serum assays after local footpad injection revealed that the bispecific antibody had improved skin retention, faster elimination from the blood, and less systemic IFN-γ inhibition than the nontethered version. Furthermore, the bispecific antibody conferred localized protection almost exclusively to the treated footpad during vitiligo, which was not possible by local injection of the nontethered anti‒IFN-γ antibody. Thus, keratinocyte tethering proved effective while significantly diminishing the off-tissue effects of IFN-γ blockade, offering a safer treatment strategy for localized skin diseases, including vitiligo.

Aberrant activation of interferon (IFN)-γ signaling plays a key role in several autoimmune skin diseases, including lupus erythematosus, alopecia areata, vitiligo, and lichen planus. Here, we identify fully chemically modified small interfering RNAs (siRNAs) that silence the ligand binding chain of the IFN-γ receptor (IFNGR1), for the modulation of IFN-γ signaling. Conjugating these siRNAs to docosanoic acid (DCA) enables productive delivery to all major skin cell types local to the injection site, with a single dose of injection supporting effective IFNGR1 protein reduction for at least 1 month in mice. In an ex vivo model of IFN-γ signaling, DCA-siRNA efficiently inhibits the induction of IFN-γ-inducible chemokines, CXCL9 and CXCL10, in skin biopsies from the injection site. Our data demonstrate that DCA-siRNAs can be engineered for functional gene silencing in skin and establish a path toward siRNA treatment of autoimmune skin diseases.

In their book `Nudge: Improving Decisions About Health, Wealth and Happiness', Thaler and Sunstein argue that choice architectures are promising public policy interventions. This research programme motivated the creation of so-called `nudge units' which aim to apply insights from behavioural science to improve public policy. We take a close look at a meta-analysis of the evidence gathered by two of the largest and most influential nudge units using statistical techniques to detect reporting biases. We find evidence suggestive of selective reporting on the full dataset, although this pattern is not robust in subgroup analyses. We therefore additionally evaluate the public pre-analysis plans from the Office of Evaluation Sciences. We find that the analysis plans and reporting usually lack sufficient detail to evaluate (unintentional) reporting biases. Nevertheless, we identify several instances of excellent practice. We additionally highlight several improvements that would enhance the effectiveness of the pre-analysis plans and reports as a means to combat reporting biases. We believe our findings and suggestions can further improve the evidence base on which policy decisions are made.

The Valley Baseball League is a collegiate summer baseball league with 11 teams playing 42 games between June and August. Producing a schedule has proved challenging for league management, because of the odd number of teams as well as a large number of league mandates and team-specific requests. As an amateur league with limited financial resources, there is pressure to best leverage the league schedule to maximize revenue for each team. A schedule generated by mathematical programming was enthusiastically adopted for the 2020 season and significantly outperformed previous manually produced schedules.

OBJECTIVE The incidence of neonatal abstinence syndrome (NAS) has increased in recent years. Treatment approaches usually involve opioid replacement; however, the optimal treatment strategy is unknown. This study sought to determine the impact of weight- and symptom-based morphine dosing strategies on LOS and medication exposure in patients with NAS. METHODS A retrospective review was conducted from May 2015 to June 2017 at 2 NICUs within a health-system using different dosing approaches for NAS. Data were compared using Fisher exact tests for categorical data and t tests and Wilcoxon ranked sums for continuous data. RESULTS Baseline demographics were well-matched except for postmenstrual age at morphine initiation (p = 0.04). The weight-based group had a larger initial morphine dose (p < 0.001) and fewer number of steps to maximum morphine dose (p = 0.009). There were no differences between groups in LOS, number of dose adjustments, doses administered, weaning steps, maximum dose, or need to re-escalate dosing. There was also no difference between the first 3 modified Finnegan scores (MFS) after transferring patients to a neonatology service. Neonates with symptom-based dosing had a higher maximum MFS (p = 0.024). Neonates in the symptom-based group required adjunct therapy more often (p < 0.0001). CONCLUSIONS Data indicate the dosing strategy impacts number of steps to reach maximum dose and need for adjunctive therapy. Weight-based dosing may decrease the number of steps required to reach the morphine maximum dose and the need for adjunctive therapy by controlling NAS symptoms earlier.

Subacute cutaneous lupus erythematosus and chronic cutaneous lupus erythematosus are represented in the majority of cutaneous lupus subtypes, each of which has variable implications for systemic manifestations such as lupus nephritis. On dermatologic examination, subacute cutaneous lupus erythematosus and chronic cutaneous lupus erythematosus are distinct. However, it is often difficult to diagnose the subtype from histology alone. Our study utilized whole-genome microarray expression analysis on human skin samples of subacute cutaneous lupus erythematosus, on human skin samples of chronic cutaneous lupus erythematosus, and on healthy controls, along with analysis on human samples of lupus nephritis and normal kidney tissue to compare cutaneous lupus subtypes with each other as well as with lupus nephritis. The data revealed that cutaneous lupus subtypes were distinct from healthy control skin, with gene expression predominantly characterized by upregulation of IFN-1 and T-cell chemotactic genes. However, the cutaneous lupus subtypes were very similar to one another; comparative analyses revealed few statistically significant differences in gene expression. There were also distinct differences between the gene signatures of cutaneous lupus and lupus nephritis. Cutaneous lupus samples revealed gene signatures demonstrating a prominent inflammatory component that may suggest the skin as an early site of initiation of lupus pathogenesis, whereas lupus nephritis reflected the recruitment and activation of M2 macrophages and a wound healing signature.

Hydraulic structures disrupt fish migration thereby contributing to declines in fish populations around the world. Methods for piping fish upstream over dams can offer much steeper lift than conventional fishways. We describe the lifting mechanism of a tube fishway, demonstrated using numerical modelling, verified by a physical model. Efficacy is demonstrated by safely lifting two species of Australian native fish over 8 m up an embankment. Significant volumes of water can be transported from a chamber at the foot of a dam over its crest using simple conduits and two valves. Unsteady flow contributes entirely or significantly to the volume of water lifted. We explore how this piped system could be scaled up, while controlling turbulence impacts on fish. We propose new methods of characterising hydraulic efficiency for fishways that recognise the energy used and the value of the water discharged.

The accrual of cytosolic DNA leads to transcription of type I IFNs, proteolytic maturation of the IL-1 family of cytokines, and pyroptotic cell death. Caspase-1 cleaves pro-IL1β to generate mature bioactive cytokine and gasdermin D which facilitates IL-1 release and pyroptotic cell death. Absent in melanoma-2 ( AIM2 ) is a sensor of dsDNA leading to caspase-1 activation, although in human monocytes, cGAS-STING acting upstream of NLRP3 mediates the dsDNA-activated inflammasome response. In healthy human keratinocytes, AIM2 is not expressed yet caspase-1 is activated by the synthetic dsDNA mimetic poly(dA:dT). Here, we show that this response is not mediated by either AIM2 or the cGAS-STING-NLRP3 pathway and is instead dependent on NLRP1. Poly(dA:dT) is unique in its ability to activate NLRP1, as conventional linear dsDNAs fail to elicit NLRP1 activation. DsRNA was recently shown to activate NLRP1 and prior work has shown that poly(dA:dT) is transcribed into an RNA intermediate that stimulates the RNA sensor RIG-I. However, poly(dA:dT)-dependent RNA intermediates are insufficient to activate NLRP1. Instead, poly(dA:dT) results in oxidative nucleic acid damage and cellular stress, events which activate MAP3 kinases including ZAKα that converge on p38 to activate NLRP1. Collectively, this work defines a new activator of NLRP1, broadening our understanding of sensors that recognize poly(dA:dT) and advances the understanding of the immunostimulatory potential of this potent adjuvant.

Vitiligo is a chronic inflammatory autoimmune disease that targets melanocytes, causing skin de-pigmentation. A cream formulation of the Janus kinase (JAK) 1/JAK2 inhibitor, ruxolitinib demonstrated substantial re-pigmentation in a phase 2 study in adults with vitiligo. In two multinational, randomized, double-blind, vehicle-controlled phase 3 studies of adults and adolescents with vitiligo (TRuE-V1, NCT04052425; TRuE-V2, NCT04057573), ruxolitinib cream was superior to vehicle at Week 24 in the primary and all key secondary endpoints. Pooled results on achievement of ≥ 50% improvement in the Vitiligo Area Scoring Index (VASI50) by body region in TRuE-V1/TRuE-V2 were analysed and are reported herein. Patients ≥ 12 years old with nonsegmental vitiligo (NSV) with de-pigmentation covering ≤ 10% total body surface area, including a total VASI (T-VASI) score ≥ 3, were eligible for enrolment. Patients were randomized 2 : 1 to twice-daily 1·5% ruxolitinib cream or vehicle for 24 weeks, after which all patients could apply twice-daily 1·5% ruxolitinib cream through Week 52 (open-label extension). The percentage of patients achieving VASI50 was calculated for each body region [head and neck (not including face), hands, upper extremities, trunk (including genitals), lower extremities, feet] and total body (excluding face). In total, 674 patients were randomized in the TRuE-V studies (ruxolitinib cream, n = 450; vehicle, n = 224); 661 patients were included in the efficacy analysis (1 site excluded for data quality) and 569 continued in the open-label extension (ruxolitinib cream from Day 1, n = 385; crossover from vehicle, n = 184). At Week 12, more patients who applied 1·5% ruxolitinib cream vs. vehicle achieved VASI50 in the head and neck (28·3% vs. 19·8%), upper extremities (14·1% vs. 11·0%), trunk (15·5% vs. 12·9%) and lower extremities (15·1% vs. 10·9%). At Week 24, more patients who applied 1·5% ruxolitinib cream vs. vehicle achieved VASI50 regardless of body region [head and neck, 45·3% vs. 23·8%; hands, 24·9% vs. 14·4%; upper extremities, 33·2% vs. 8·2%; trunk, 26·4% vs. 12·3%; lower extremities, 29·5% vs. 12·2%; feet, 18·5% vs. 12·5%; total body (excluding face), 20·8% vs. 6·9%]. Similarly at Week 52 more patients who applied ruxolitinib cream from Day 1 achieved VASI50 than those who switched over from vehicle after Week 24 (head and neck, 68·1% vs. 51·0%; hands, 38·2% vs. 29·2%; upper extremities, 56·7% vs. 34·9%; trunk, 48·4% vs. 25·4%; lower extremities, 54·5% vs. 32·3%; feet, 29·3% vs. 22·5%; total body [excluding face], 47·7% vs. 23·3%). Attainment of VASI50 at Week 52 among crossover patients (i.e. after 28 weeks of ruxolitinib cream) was consistent with Week 24 data in patients who applied ruxolitinib cream from Day 1. Adolescents and adults with NSV applying ruxolitinib cream achieved VASI50 in higher percentages compared with vehicle at Week 12 in the head and neck, upper extremities, trunk and lower extremities and at Week 24, regardless of the body region involved. The percentage of patients who achieved VASI50 increased through Week 52, including among patients who switched over from vehicle to ruxolitinib cream after Week 24. In summary, ruxolitinib cream produced a clinically meaningful re-pigmentation of all body regions (including hands and feet that are notoriously difficult to re-pigment) in TRuE-V1/TruE-V2 through Week 52, including among patients who switched over to ruxolitinib cream from vehicle after Week 24.

BackgroundSyndromic surveillance systems are an essential component of public health surveillance and can provide timely detection of infectious disease cases and outbreaks. Whilst surveillance systems are generally embedded within healthcare, there is increasing interest in novel data sources for monitoring trends in illness, such as over-the-counter purchases, internet-based health searches and worker absenteeism. This systematic review considers the utility of school attendance registers in the surveillance of infectious disease outbreaks and occurrences amongst children.MethodsWe searched eight databases using key words related to school absence, infectious disease and syndromic surveillance. Studies were limited to those published after 1st January 1995. Studies based in nursery schools or higher education settings were excluded. Article screening was undertaken by two independent reviewers using agreed eligibility criteria. Data extraction was performed using a standardised data extraction form. Outcomes included estimates of absenteeism, correlation with existing surveillance systems and associated lead or lag times.ResultsFifteen studies met the inclusion criteria, all of which were concerned with the surveillance of influenza. The specificity of absence data varied between all-cause absence, illness absence and syndrome-specific absence. Systems differed in terms of the frequency of data submissions from schools and the level of aggregation of the data. Baseline rates of illness absence varied between 2.3–3.7%, with peak absences ranging between 4.1–9.8%. Syndrome-specific absenteeism had the strongest correlation with other surveillance systems (r = 0.92), with illness absenteeism generating mixed results and all-cause absenteeism performing the least well. A similar pattern of results emerged in terms of lead and lag times, with influenza-like illness (ILI)-specific absence providing a 1–2 week lead time, compared to lag times reported for all-cause absence data and inconsistent results for illness absence data.ConclusionSyndrome-specific school absences have potential utility in the syndromic surveillance of influenza, demonstrating good correlation with healthcare surveillance data and a lead time of 1–2 weeks ahead of existing surveillance measures. Further research should consider the utility of school attendance registers for conditions other than influenza, to broaden our understanding of the potential application of this data for infectious disease surveillance in children.Systematic review registrationPROSPERO 2019 CRD42019119737.

BACKGROUND: Vitiligo is a chronic autoimmune disease that causes skin depigmentation. A cream formulation of ruxolitinib (an inhibitor of Janus kinase 1 and 2) resulted in repigmentation in a phase 2 trial involving adults with vitiligo. METHODS: We conducted two phase 3, double-blind, vehicle-controlled trials (Topical Ruxolitinib Evaluation in Vitiligo Study 1 [TRuE-V1] and 2 [TRuE-V2]) in North America and Europe that involved patients 12 years of age or older who had nonsegmental vitiligo with depigmentation covering 10% or less of total body-surface area. Patients were randomly assigned in a 2:1 ratio to apply 1.5% ruxolitinib cream or vehicle control twice daily for 24 weeks to all vitiligo areas on the face and body, after which all patients could apply 1.5% ruxolitinib cream through week 52. The primary end point was a decrease (improvement) of at least 75% from baseline in the facial Vitiligo Area Scoring Index (F-VASI; range, 0 to 3, with higher scores indicating a greater area of facial depigmentation), or F-VASI75 response, at week 24. There were five key secondary end points, including improved responses on the Vitiligo Noticeability Scale. RESULTS: A total of 674 patients were enrolled, 330 in TRuE-V1 and 344 in TRuE-V2. In TRuE-V1, the percentage of patients with an F-VASI75 response at week 24 was 29.8% in the ruxolitinib-cream group and 7.4% in the vehicle group (relative risk, 4.0; 95% confidence interval [CI], 1.9 to 8.4; P

People exhibit scope insensitivity: their expressed valuation of a problem is not proportionate with its scope or size. To address scope insensitivity in charitable giving, Hsee et al. (2013) developed the (Classical) Unit Asking technique, where people are firstasked how much they are willing to donate to support a single individual, followed by how much they are willing to donate to support a group of individuals. In this paper, we explored the mechanisms, extensions, and limitations of the technique. In particular, we investigated an extension of the technique, which we all Sequential Unit Asking (SUA). SUA asks people a series of willingness-to-donate questions, in which the number of individuals to be helped increases in a stepwise manner until it reaches the total group size. Across four studies investigating donation judgements (total N = 2045), we did not find evidence that Willingness to Donate (WTD) judgements to the total group increased with larger groups. Instead, our results suggest that Unit Asking (sequential or classical) increases donation amounts only through a single one-off boost. Further, we find evidence in three out of four studies that the Sequential Unit Asking extension increases WTD judgements over Classical Unit Asking. In a fifth study (N = 537) using a contingent valuation design (instead of donation judgements), we find scope sensitivity using all asking techniques. We conclude that, whilst it is difficult to create scope sensitivity in WTD judgements, SUA should be considered a promising approach to increase charitable donations.