Background: Trofinetide significantly improved core symptoms of Rett syndrome (RTT) with an acceptable safety profile in LAVENDER. Here, we report the safety and efficacy results of LILAC and LILAC-2, open-label extension studies of LAVENDER. Methods: Females with RTT, aged 5–21 years, received twice-daily, oral trofinetide in LILAC for 40 weeks. Participants who completed LAVENDER and LILAC continued trofinetide in LILAC-2, a 32-month extension study. Safety assessments included the incidence of adverse events (AEs). Efficacy endpoints included the Rett Syndrome Behaviour Questionnaire (RSBQ) and the Clinical Global Impression–Improvement (CGI-I) scale. Results: Overall, 154 patients were enrolled in LILAC. The most common AEs were diarrhea (74.7%) and vomiting (28.6%). The mean (standard error [SE]) change from the LAVENDER baseline to Week 40 in the LILAC study in RSBQ was -7.3 (1.62) and -7.0 (1.61) for participants treated with trofinetide and placebo in LAVENDER, respectively. Mean (SE) CGI-I scores compared with the LILAC baseline at Week 40 were 3.1 (0.11) and 3.2 (0.14) for patients treated with trofinetide and placebo in LAVENDER, respectively. Similar safety and efficacy trends were observed in LILAC-2. Conclusions: Trofinetide continued to improve symptoms of RTT in LILAC and LILAC-2 with a safety profile consistent with LAVENDER.

This article presents a short summary of the conclusions we report in a longer manuscript (available in our Supplementary Material) subjecting Lagodny et al.’s new measure of state policy mood to the same set of face validity and construct validity tests we applied earlier to Enns and Koch’s measure. We encourage readers to read this longer manuscript, which contains not only the conclusions herein, but also the evidence justifying these conclusions, before accepting or rejecting any claims we make. Our results show that the characteristics of Enns and Koch’s measure that led us to be doubtful that it is valid are also present in Lagodny et al.’s new measure – leaving us just as doubtful that Lagodny et al.’s measure is valid. Moreover, the low correlation between Lagodny et al.’s measure and Enns and Koch’s measure, combined with evidence from replications of seven published studies that the two measures frequently yield quite different inferences about the impact of policy mood on public policy, indicate that Lagodny et al.’s claim that both their measure and Enns and Koch’s measure are valid is wrong; either neither measure is valid, or one is valid and the other is not. Moreover, extending the replications to include not only Lagodny et al.’s and Enns and Koch’s measures, but also Berry et al.’s measure and Caughey and Warshaw’s measure of mass economic liberalism, shows that each of the four measures yields a substantive conclusion about the effect of policy mood that is dramatically different than each of the other three measures. This suggests that the goal of developing a measure of state policy mood that would be widely accepted as valid remains elusive.

Enns and Koch question the validity of the Berry, Ringquist, Fording, and Hanson measure of state policy mood and defend the validity of the Enns and Koch measure on two grounds. First, they claim policy mood has become more conservative in the South over time; we present empirical evidence to the contrary: policy mood became more liberal in the South between 1980 and 2010. Second, Enns and Koch argue that an indicator’s lack of face validity in cross-sectional comparisons is irrelevant when judging the measure’s suitability in the most common form of pooled cross-sectional time-series analysis. We show their argument is logically flawed, except under highly improbable circumstances. We also demonstrate, by replicating several published studies, that statistical results about the effect of state policy mood can vary dramatically depending on which of the two mood measures is used, making clear that a researcher’s measurement choice can be highly consequential.

The lift and drag forces acting on a small spherical particle moving with a finite slip in single-wall-bounded flows are investigated via direct numerical simulations. This study is an extension of our previous work that considered the lift and drag forces acting on a sphere moving near a wall in the presence shear, but in the absence of slip (Ekanayake et al., J. Fluid Mech., vol. 904, 2020, A6). The effect of slip velocity on the particle force is analysed as a function of separation distance for low slip and shear Reynolds numbers ($10^{-3} \leq Re_{{slip}} \leq 10^{-1}$ and $10^{-3} \leq Re_{\gamma } \leq 10^{-1}$) in both quiescent and linear shear flows. A generalised lift model valid for arbitrary particle–wall separation distances and $Re_{\gamma }, Re_{{slip}} \leq 10^{-1}$ is developed based on the results of the simulations. The proposed model can now predict the lift forces in linear shear flows in the presence or absence of slip, and in quiescent flows when slip is present. Existing drag models are also compared with numerical results for both quiescent and linear shear flows to determine which models capture near-wall slip velocities most accurately for low particle Reynolds numbers. Finally, we compare the results of the proposed lift model to previous experimental results of negatively buoyant particles and to numerical results of neutrally buoyant (force-free) particles moving near a wall in quiescent and linear shear flows. The generalised lift model presented can be used to predict the behaviour of particle suspensions in biological and industrial flows where the particle Reynolds numbers based on slip and shear are ${O}(10^{-1})$ and below.

Medical care is predicated on ‘do no harm’, yet the urgency to find drugs and vaccines to treat or prevent COVID-19 has led to an extraordinary effort to develop and test new therapies. Whilst this is an essential cornerstone of a united global response to the COVID-19 pandemic, the absolute requirements for meticulous efficacy and safety data remain. This is especially pertinent to the needs of pregnant women; a group traditionally poorly represented in drug trials, yet a group at heightened risk of unintended adverse materno-fetal consequences due to the unique physiology of pregnancy and the life course implications of fetal or neonatal drug exposure. However, due to the complexities of drug trial participation when pregnant (be they vaccines or therapeutics for acute disease), many clinical drug trials will exclude them. Clinicians must determine the best course of drug treatment with a dearth of evidence from either clinical or preclinical studies, where at least in the short term they may be more focused on the outcome of the mother than of her offspring.

CVD is the leading cause of death worldwide and, after dementia, is the second biggest cause of death for women. In England, it accounts for one in four of all deaths. Lifestyle modifications represent the primary route both to reduce CVD risk factors and prevent CVD outcomes. Diet constitutes one of the key modifiable risk factors in the aetiology of CVD. We investigated the relationship between nine main dietary indices and a comprehensive range of CVD risk factors in 2590 women from TwinsUK. After adjustment for multiple testing, we found that the Dietary Approaches to Stop Hypertension (DASH) diet was inversely correlated with some of the most common CVD risk factors (BMI, visceral fat (VF), TAG, insulin, homoeostasis model assessment of insulin resistance (HOMA2-IR) and atherosclerotic CVD (ASCVD) risk) with PFDR ranging from 6·28 × 10−7 to 5·63 × 10−4. Similar association patterns were detected across most of the dietary indices analysed. In our post hoc investigation, to determine if any specific food groups were driving associations between the DASH score and markers of cardiometabolic risk, we found that increased BMI, VF, HOMA2-IR, ASCVD risk, insulin and TAG levels were directly correlated with red meat consumption (PFDR ranging from 4·65 × 10−9 to 7·98 × 10−3) and inversely correlated with whole-grain cereal consumption (PFDR ranging from 1·26 × 10−6 to 8·28 × 10−3). Our findings revealed that the DASH diet is associated with a more favourable CVD risk profile, suggesting that this diet may be a candidate dietary pattern to supplement current UK dietary recommendations for CVD prevention.

The lift and drag forces acting on a small spherical particle in a single wall-bounded linear shear flow are examined via numerical computation. The effects of shear rate are isolated from those of slip by setting the particle velocity equal to the local fluid velocity (zero slip), and examining the resulting hydrodynamic forces as a function of separation distance. In contrast to much of the previous numerical literature, low shear Reynolds numbers are considered ($10^{-3} \lesssim Re_{\gamma } \lesssim 10^{-1}$). This shear rate range is relevant when dealing with particulate flows within small channels, for example particle migration in microfluidic devices being used or developed for the biotech industry. We demonstrate a strong dependence of both the lift and drag forces on shear rate. Building on previous theoretical $Re_{\gamma } \ll 1$ studies, a wall-shear-based zero-slip lift correlation is proposed that is applicable when the wall lies both within the inner and outer regions of the disturbed flow. Similarly, we validate an improved wall-shear-based zero-slip drag correlation that more accurately captures the drag force when the particle is close to, but not touching, the wall. Application of the new correlations to predict the movement of a force-free particle shows that the examined shear-based lift force is as important as the previously examined slip-based lift force, highlighting the need to accurately account for shear when predicting the near-wall movement of force-free particles.

The net benefit from investing in any technology is a function of the cost of implementation and the expected return in revenue. The objective of the present study was to quantify, using deterministic equations, the net monetary benefit from investing in genotyping of commercial females. Three case studies were presented reflecting dairy cows, beef cows and ewes based on Irish population parameters; sensitivity analyses were also performed. Parameters considered in the sensitivity analyses included the accuracy of genomic evaluations, replacement rate, proportion of female selection candidates retained as replacements, the cost of genotyping, the sire parentage error rate and the age of the female when it first gave birth. Results were presented as an annualised monetary net benefit over the lifetime of an individual, after discounting for the timing of expressions. In the base scenarios, the net benefit was greatest for dairy, followed by beef and then sheep. The net benefit improved as the reliability of the genomic evaluations improved and, in fact, a negative net benefit of genotyping was less frequent when the reliability of the genomic evaluations was high. The impact of a 10% point increase in genomic reliability was, however, greatest in sheep, followed by beef and then dairy. The net benefit of genotyping female selection candidates reduced as replacement rate increased. As genotyping costs increased, the net benefit reduced irrespective of the percentage of selection candidates kept, the replacement rate or even the population considered. Nonetheless, the association between the genotyping cost and the net benefit of genotyping differed by the percentage of selection candidates kept. Across all replacement rates evaluated, retaining 25% of the selection candidates resulted in the greatest net benefit when genotyping cost was low but the lowest net benefit when genotyping cost was high. Genotyping breakeven cost was non-linearly associated with the percentage of selection candidates retained, reaching a maximum when 50% of selection candidates were retained, irrespective of replacement rate, genomic reliability or the population. The genotyping breakeven cost was also non-linearly associated with replacement rate. The approaches outlined within provide the back-end framework for a decision support tool to quantify the net benefit of genotyping, once parameterised by the relevant population metrics.

Knowledge of population structure and breed composition of a population can be advantageous for a number of reasons; these include designing optimal (cross)breeding strategies in order to maximise non-additive genetic effects, maintaining flockbook integrity by authenticating animals being registered and as a quality control measure in the genotyping process. The objectives of the present study were to 1) describe the population structure of 24 sheep breeds, 2) quantify the breed composition of both flockbook-recorded and crossbred animals using single nucleotide polymorphism BLUP (SNP-BLUP), and 3) quantify the accuracy of breed composition prediction from low-density genotype panels containing between 2000 and 6000 SNPs. In total, 9334 autosomal SNPs on 11 144 flockbook-recorded animals and 1172 crossbred animals were used. The population structure of all breeds was characterised by principal component analysis (PCA) as well as the pairwise breed fixation index (Fst). The total number of animals, all of which were purebred, included in the calibration population for SNP-BLUP was 2579 with the number of animals per breed ranging from 9 to 500. The remaining 9559 flockbook-recorded animals, composite breeds and crossbred animals represented the test population; three breeds were excluded from breed composition prediction. The breed composition predicted using SNP-BLUP with 9334 SNPs was considered the gold standard prediction. The pairwise breed Fst ranged from 0.040 (between the Irish Blackface and Scottish Blackface) to 0.282 (between the Border Leicester and Suffolk). Principal component analysis revealed that the Suffolk from Ireland and the Suffolk from New Zealand formed distinct, non-overlapping clusters. In contrast, the Texel from Ireland and that from New Zealand formed integrated, overlapping clusters. Composite animals such as the Belclare clustered close to its founder breeds (i.e., Finn, Galway, Lleyn and Texel). When all 9334 SNPs were used to predict breed composition, an animal that had a majority breed proportion predicted to be ≥0.90 was defined as purebred for the present study. As the panel density decreased, the predicted breed proportion threshold, used to identify animals as purebred, also decreased (≥0.85 with 6000 SNPs to ≥0.60 with 2000 SNPs). In all, results from the study suggest that breed composition for purebred and crossbred animals can be determined with SNP-BLUP using ≥5000 SNPs.

Poor compliance of prescription medication is an ongoing public health crisis. Nearly half of patients do not take their medication as prescribed, harming their own health while also increasing public health care costs. Despite these detrimental consequences, prior research has struggled to establish cost-effective and scalable interventions to improve adherence rates. We suggest that one reason for the limited success of prior interventions is that they make the personal health costs of non-adherence insufficiently prominent, while a higher saliency of these costs may motivate patients to adhere more. In the current research, we test whether an intervention that makes the personal health costs of non-compliance more salient for patients will increase their medication adherence. To do so, we conducted a randomized controlled trial with 16,191 patients across 278 UK pharmacies over a 9-month time period and manipulated the perceived consequences of medication non-adherence. We find that patients who received a treatment highlighting the personal health costs of non-compliance were significantly more likely to adhere to their medication than three comparison groups (odds ratio = 1.84, 95% confidence interval = 1.37–2.47). Shifting patients’ focus to the personal health costs of non-compliance may thus offer a potentially cost-effective and scalable approach to improving medication adherence.

Although food from grazed animals is increasingly sought by consumers because of perceived animal welfare advantages, grazing systems provide the farmer and the animal with unique challenges. The system is dependent almost daily on the climate for feed supply, with the importation of large amounts of feed from off farm, and associated labour and mechanisation costs, sometimes reducing economic viability. Furthermore, the cow may have to walk long distances and be able to harvest feed efficiently in a highly competitive environment because of the need for high levels of pasture utilisation. She must, also, be: (1) highly fertile, with a requirement for pregnancy within ~80 days post-calving; (2) ‘easy care’, because of the need for the management of large herds with limited labour; (3) able to walk long distances; and (4) robust to changes in feed supply and quality, so that short-term nutritional insults do not unduly influence her production and reproduction cycles. These are very different and are in addition to demands placed on cows in housed systems offered pre-made mixed rations. Furthermore, additional demands in environmental sustainability and animal welfare, in conjunction with the need for greater system-level biological efficiency (i.e. ‘sustainable intensification’), will add to the ‘robustness’ requirements of cows in the future. Increasingly, there is evidence that certain genotypes of cows perform better or worse in grazing systems, indicating a genotype×environment interaction. This has led to the development of tailored breeding objectives within countries for important heritable traits to maximise the profitability and sustainability of their production system. To date, these breeding objectives have focussed on the more easily measured traits and those of highest relative economic importance. In the future, there will be greater emphasis on more difficult to measure traits that are important to the quality of life of the animal in each production system and to reduce the system’s environmental footprint.

This paper describes three case examples from a recent trial of family intervention specifically designed for people of African-Caribbean descent. These examples, told from the therapists’ perspectives, highlight key components of the intervention and issues that arose in working with this client group. Findings from the study suggest that it is possible to engage this client-group in family therapy similar to traditional evidenced-based family interventions, although as illustrated in the paper, it is important that therapists pay attention to themes that are likely to be particularly pertinent for this group, including experiences of discrimination and mistrust of services. The use of Family Support Members, consisting of members of the person's care team or volunteers recruited from the community, may also help support people to engage in therapy in the absence of biological relatives.

Body condition score (BCS) is a subjective assessment of the proportion of body fat an animal possesses and is independent of frame size. There is a growing awareness of the importance of mature animal live-weight given its contribution to the overall costs of production of a sector. Because of the known relationship between BCS and live-weight, strategies to reduce live-weight could contribute to the favouring of animals with lesser body condition. The objective of the present study was to estimate the average difference in live-weight per incremental change in BCS, measured subjectively on a scale of 1 to 5. The data used consisted of 19 033 BCS and live-weight observations recorded on the same day from 7556 ewes on commercial and research flocks; the breeds represented included purebred Belclare (540 ewes), Charollais (1484 ewes), Suffolk (885 ewes), Texel (1695 ewes), Vendeen (140 ewes), as well as, crossbreds (2812 ewes). All associations were quantified using linear mixed models with the dependent variable of live-weight; ewe parity was included as a random effect. The independent variables were BCS, breed (n=6), stage of the inter-lambing interval (n=6; pregnancy, lambing, pre-weaning, at weaning, post-weaning and mating) and parity (1, 2, 3, 4 and 5+). In addition, two-way interactions were used to investigate whether the association between BCS and live-weight differed by parity, a period of the inter-lambing interval or breed. The association between BCS and live-weight differed by parity, by a period of the inter-lambing interval and by breed. Across all data, a one-unit difference in BCS was associated with 4.82 (SE=0.08) kg live-weight, but this differed by parity from 4.23 kg in parity 1 ewes to 5.82 kg in parity 5+ ewes. The correlation between BCS and live-weight across all data was 0.48 (0.47 when adjusted for nuisance factors in the statistical model), but this varied from 0.48 to 0.53 by parity, from 0.36 to 0.63 by stage of the inter-lambing interval and from 0.41 to 0.62 by breed. Results demonstrate that consideration should be taken of differences in BCS when comparing ewes on live-weight as differences in BCS contribute quite substantially to differences in live-weight; moreover, adjustments for differences in BCS should consider the population stratum, especially breed.

Understanding how critical sow live-weight and back-fat depth during gestation are in ensuring optimum sow productivity is important. The objective of this study was to quantify the association between sow parity, live-weight and back-fat depth during gestation with subsequent sow reproductive performance. Records of 1058 sows and 13 827 piglets from 10 trials on two research farms between the years 2005 and 2015 were analysed. Sows ranged from parity 1 to 6 with the number of sows per parity distributed as follows: 232, 277, 180, 131, 132 and 106, respectively. Variables that were analysed included total born (TB), born alive (BA), piglet birth weight (BtWT), pre-weaning mortality (PWM), piglet wean weight (WnWT), number of piglets weaned (Wn), wean to service interval (WSI), piglets born alive in subsequent farrowing and sow lactation feed intake. Calculated variables included the within-litter CV in birth weight (LtV), pre-weaning growth rate per litter (PWG), total litter gain (TLG), lactation efficiency and litter size reared after cross-fostering. Data were analysed using linear mixed models accounting for covariance among records. Third and fourth parity sows had more (P<0.05) TB, BA and heavier BtWT compared with gilts and parity 6 sow contemporaries. Parities 2 and 3 sows weaned more (P<0.05) piglets than older sows. These piglets had heavier (P<0.05) birth weights than those from gilt litters. LtV and PWM were greater (P<0.01) in litters born to parity 5 sows than those born to younger sows. Sow live-weight and back-fat depth at service, days 25 and 50 of gestation were not associated with TB, BA, BtWT, LtV, PWG, WnWT or lactation efficiency (P>0.05). Heavier sow live-weight throughout gestation was associated with an increase in PWM (P<0.01) and reduced Wn and lactation feed intake (P<0.05). Deeper back-fat in late gestation was associated with fewer (P<0.05) BA but heavier (P<0.05) BtWT, whereas deeper back-fat depth throughout gestation was associated with reduced (P<0.01) lactation feed intake. Sow back-fat depth was not associated with LtV, PWG, TLG, WSI or piglets born alive in subsequent farrowing (P>0.05). In conclusion, this study showed that sow parity, live-weight and back-fat depth can be used as indicators of reproductive performance. In addition, this study also provides validation for future development of a benchmarking tool to monitor and improve the productivity of modern sow herd.