Comparative Effectiveness and Durability of Biologics in Clinical Practice: Month 12 Outcomes from the International, Observational Psoriasis Study of Health Outcomes (PSoHO).

INTRODUCTION: Given the chronic nature of psoriasis (PsO), more studies are needed that directly compare the effectiveness of different biologics over long observation periods. This study compares the effectiveness and durability through 12 months of anti-interleukin (IL)-17A biologics relative to other approved biologics in patients with moderate-to-severe psoriasis in a real-world setting. METHODS: The Psoriasis Study of Health Outcomes (PSoHO) is an ongoing 3-year, prospective, non-interventional cohort study of 1981 adults with chronic moderate-to-severe plaque psoriasis initiating or switching to a new biologic. The study compares the effectiveness of anti-IL-17A biologics with other approved biologics and provides pairwise comparisons of seven individual biologics versus ixekizumab. The primary outcome was defined as the proportion of patients who had at least a 90% improvement in Psoriasis Area and Severity Index score (PASI90) and/or a score of 0 or 1 in static Physician Global Assessment (sPGA). Secondary objective comparisons included the proportion of patients who achieved PASI90, PASI100, a Dermatology Life Quality Index (DLQI) score of 0 or 1, and three different actions of durability of treatment response. Unadjusted response rates are presented alongside the primary analysis, which uses frequentist model averaging (FMA) to evaluate the adjusted comparative effectiveness. RESULTS: Compared to the other biologics cohort, the anti-IL-17A cohort had a higher response rate (68.0% vs. 65.1%) and significantly higher odds of achieving the primary outcome at month 12. The two cohorts had similar response rates for PASI100 (40.5% and 37.1%) and PASI90 (53.9% and 51.7%) at month 12, with no significant differences between the cohorts in the adjusted analyses. At month 12, the response rates across the individual biologics were 53.5-72.6% for the primary outcome, 27.6-48.3% for PASI100, and 41.7-61.4% for PASI90. CONCLUSIONS: These results show the comparative effectiveness of biologics at 6 and 12 months in the real-world setting. TRIAL REGISTRATION: ClinicalTrials.gov identifier EUPAS24207.

Assessing complexity and dynamics in epidemics: geographical barriers and facilitators of foot-and-mouth disease dissemination.

Introduction: Physical and non-physical processes that occur in nature may influence biological processes, such as dissemination of infectious diseases. However, such processes may be hard to detect when they are complex systems. Because complexity is a dynamic and non-linear interaction among numerous elements and structural levels in which specific effects are not necessarily linked to any one specific element, cause-effect connections are rarely or poorly observed. Methods: To test this hypothesis, the complex and dynamic properties of geo-biological data were explored with high-resolution epidemiological data collected in the 2001 Uruguayan foot-and-mouth disease (FMD) epizootic that mainly affected cattle. County-level data on cases, farm density, road density, river density, and the ratio of road (or river) length/county perimeter were analyzed with an open-ended procedure that identified geographical clustering in the first 11 epidemic weeks. Two questions were asked: (i) do geo-referenced epidemiologic data display complex properties? and (ii) can such properties facilitate or prevent disease dissemination? Results: Emergent patterns were detected when complex data structures were analyzed, which were not observed when variables were assessed individually. Complex properties-including data circularity-were demonstrated. The emergent patterns helped identify 11 counties as 'disseminators' or 'facilitators' (F) and 264 counties as 'barriers' (B) of epidemic spread. In the early epidemic phase, F and B counties differed in terms of road density and FMD case density. Focusing on non-biological, geographical data, a second analysis indicated that complex relationships may identify B-like counties even before epidemics occur. Discussion: Geographical barriers and/or promoters of disease dispersal may precede the introduction of emerging pathogens. If corroborated, the analysis of geo-referenced complexity may support anticipatory epidemiological policies.

Systematic Review of Variables Related to Instruction in Augmentative and Alternative Communication Implementation: Group and Single-Case Design.

PURPOSE: This article provides a systematic review and analysis of group and single-case studies addressing augmentative and alternative communication (AAC) intervention with school-aged persons having autism spectrum disorder (ASD) and/or intellectual/developmental disabilities resulting in complex communication needs (CCNs). Specifically, we examined participant characteristics in group-design studies reporting AAC intervention outcomes and how these compared to those reported in single-case experimental designs (SCEDs). In addition, we compared the status of intervention features reported in group and SCED studies with respect to instructional strategies utilized. PARTICIPANTS: Participants included school-aged individuals with CCNs who also experienced ASD or ASD with an intellectual delay who utilized aided or unaided AAC. METHOD: A systematic review using descriptive statistics and effect sizes was implemented. RESULTS: Findings revealed that participant features such as race, ethnicity, and home language continue to be underreported in both SCED and group-design studies. Participants in SCED investigations more frequently used multiple communication modes when compared to participants in group studies. The status of pivotal skills such as imitation was sparsely reported in both types of studies. With respect to instructional features, group-design studies were more apt to utilize clinical rather than educational or home settings when compared with SCED studies. In addition, SCED studies were more apt to utilize instructional methods that closely adhered to instructional features more typically characterized as being associated with behavioral approaches. CONCLUSION: The authors discuss future research needs, practice implications, and a more detailed specification of treatment intensity parameters for future research.

Participant characteristics predicting communication outcomes in AAC implementation for individuals with ASD and IDD: a systematic review and meta-analysis.

This meta-analysis examined communication outcomes in single-case design studies of augmentative and alternative communication (AAC) interventions and their relationship to participant characteristics. Variables addressed included chronological age, pre-intervention communication mode, productive repertoire, and pre-intervention imitation skills. Investigators identified 114 single-case design studies that implemented AAC interventions with school-aged individuals with autism spectrum disorder and/or intellectual disability. Two complementary effect size indices, Tau(AB) and the log response ratio, were applied to synthesize findings. Both indices showed positive effects on average, but also exhibited a high degree of heterogeneity. Moderator analyses detected few differences in effectiveness when comparing across diagnoses, age, the number and type of communication modes, participant's productive repertoires, and imitation skills to intervention. A PRISMA-compliant abstract is available: https://bit.ly/30BzbLv.

Corrigendum to: The acute physiological status of white sharks (Carcharodon carcharias) exhibits minimal variation after capture on SMART drumlines.

[This corrects the article DOI: 10.1093/conphys/coz042.].

The acute physiological status of white sharks (Carcharodon carcharias) exhibits minimal variation after capture on SMART drumlines.

Drumlines incorporating SMART (Shark-Management-Alert-in-Real-Time) technology are a new tool used in several bather protection programmes globally. In New South Wales (NSW), Australia, the white shark (Carcharodon carcharias) is a target species for SMART drumlines because they are often involved in attacks on humans. To understand white shark sensitivity to capture and to establish protocols around acceptable timeframes for responding to alerts, 47 juvenile and subadult white sharks were caught on SMART drumlines at five locations off the east coast of Australia. There was no at-vessel mortality during the sampling period. After capture, blood was sampled from each shark to assess its acute physiological status. Of the 18 metabolites investigated, only lactate and aspartate aminotransferase exhibited significant positive relationships with the capture duration on SMART drumlines. These results indicate that the capture process is relatively benign and that the current response times used here are appropriate to minimize long-term negative impacts on released white sharks. Where white sharks are likely to interact negatively with beachgoers, SMART drumlines can therefore be a useful addition to bather protection programmes that also aim to minimize harm to captured animals. Other shark species captured on SMART drumlines should also be investigated to gain broader understanding of potential physiological consequences of using this new technology.

Computational Modeling of Anthocyanin Pathway Evolution: Biases, Hotspots, and Trade-offs.

The alteration of metabolic pathways is a common mechanism underlying the evolution of new phenotypes. Flower color is a striking example of the importance of metabolic evolution in a complex phenotype, wherein shifts in the activity of the underlying pathway lead to a wide range of pigments. Although experimental work has identified common classes of mutations responsible for transitions among colors, we lack a unifying model that relates pathway function and activity to the evolution of distinct pigment phenotypes. One challenge in creating such a model is the branching structure of pigment pathways, which may lead to evolutionary trade-offs due to competition for shared substrates. In order to predict the effects of shifts in enzyme function and activity on pigment production, we created a simple kinetic model of a major plant pigmentation pathway: the anthocyanin pathway. This model describes the production of the three classes of blue, purple, and red anthocyanin pigments, and accordingly, includes multiple branches and substrate competition. We first studied the general behavior of this model using a naïve set of parameters. We then stochastically evolved the pathway toward a defined optimum and analyzed the patterns of fixed mutations. This approach allowed us to quantify the probability density of trajectories through pathway state space and identify the types and number of changes. Finally, we examined whether our simulated results qualitatively align with experimental observations, i.e., the predominance of mutations which change color by altering the function of branching genes in the pathway. These analyses provide a theoretical framework that can be used to predict the consequences of new mutations in terms of both pigment phenotypes and pleiotropic effects.

Hidradenitis suppurativa and diabetes mellitus: updated systematic review and adjusted meta-analysis.

BACKGROUND: Hidradenitis suppurativa (HS) is a debilitating and distressing chronic inflammatory skin disease. There is also evolving evidence supporting the association between HS and cardiovascular risk factors, including smoking, obesity, hyperlipidaemia and metabolic syndrome. Notably, these are clinical features and risk factors that are closely associated with type 2 diabetes mellitus (DM). AIMS: We performed a pooled adjusted meta-analysis of comparative studies to investigate the relationship between HS and DM. METHODS: A systematic review and meta-analysis was performed according to recommended Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. OR was used as the summary effect size. RESULTS: From pooled analysis of unadjusted data from 12 studies, we found a significantly higher proportion of DM in HS cases compared with non-HS healthy controls (16.1% vs. 15.7%; OR = 2.17; 95% CI 1.85-2.55; P < 0.001). Adjusted effect sizes from five studies were also pooled. A significantly higher proportion of DM was found for HS compared with healthy controls, although the effect size was attenuated compared with unadjusted analyses (OR 1.69; 95% CI 1.50-1.91; P < 0.001). CONCLUSIONS: To our knowledge, our systematic review and meta-analysis is the first to pool adjusted effect sizes. We found that HS was associated with a 1.69-fold increased odds of diabetes; however, the absolute risk difference was small (16.1% vs. 15.7%) and is probably not clinically relevant. Treating clinicians should be aware of this association, but there may not be an urgent need to perform screening for impaired glucose tolerance or diabetes.

Probiotic Lactococcus lactis decreases incidence and severity of necrotizing enterocolitis in a preterm animal model.

BACKGROUND: Necrotizing enterocolitis (NEC) persists as the most common and serious gastrointestinal disorder among premature infants. Lactococcus lactis (LL), a lactic acid producing bacteria commonly found in buttermilk and cheese products, has several unique properties making it an ideal probiotic for neonates. We evaluated if the probiotic LL prevents development of NEC in a preterm rabbit model with Cronobacter sakazakii (CS). METHODS: Two-day preterm New Zealand white rabbit pups were randomly assigned to three diets: control (no additives), CS, and CS+LL. Pups were gavage fed and given daily oral ranitidine and indomethacin. Anal blockage was performed using tissue adhesive. Subjects were sacrificed on day four, with tissue from distal ileum and proximal colon graded for NEC by a pediatric pathologist blinded to group assignments. Outcomes were compared using Fisher's exact test. RESULTS: All pups in the control group survived to sacrifice and none developed NEC. Survival was 26% higher (p = 0.03) and incidence of NEC 51% less (P < 0.001) in CS+LL group compared to CS group. Of the pups that developed NEC, all pups in the CS+LL group had Grade 1 NEC, while one-third of pups in the CS group developed Grades 2-4 NEC. CONCLUSIONS: In the presence of CS, LL is protective against development of NEC in a preterm rabbit model. Future studies are needed that evaluate utilization of prophylactic probiotics in the neonatal intensive care unit to determine if this intervention can successfully decrease rates of NEC in preterm infants.

Itching for nail fashion: chronic urticaria and chronic hand dermatitis secondary to acrylate and methacrylate allergy in gel nail varnish.

Allergic contact dermatitis (ACD) secondary to acrylates and methacrylates is a well- described occurrence, particularly in those who wear or handle gel nail varnish. Management involves avoidance of the identified allergen. The cause of chronic urticaria (CI) is often not identified, and CU is not known to be associated with acrylates or methacrylates. We report a case of a 50-year-old woman who initially presented with hand dermatitis exacerbated by gel nail varnish on a background of CU. Avoiding all nail varnishes because of her ACD also resulted in improvement of her CU. To our knowledge, this is the first documented case of CU secondary to the acrylates and methacrylates found in nail cosmetics.

Next-gen sequencing identifies non-coding variation disrupting miRNA-binding sites in neurological disorders.

Understanding the genetic factors underlying neurodevelopmental and neuropsychiatric disorders is a major challenge given their prevalence and potential severity for quality of life. While large-scale genomic screens have made major advances in this area, for many disorders the genetic underpinnings are complex and poorly understood. To date the field has focused predominantly on protein coding variation, but given the importance of tightly controlled gene expression for normal brain development and disorder, variation that affects non-coding regulatory regions of the genome is likely to play an important role in these phenotypes. Herein we show the importance of 3 prime untranslated region (3'UTR) non-coding regulatory variants across neurodevelopmental and neuropsychiatric disorders. We devised a pipeline for identifying and functionally validating putatively pathogenic variants from next generation sequencing (NGS) data. We applied this pipeline to a cohort of children with severe specific language impairment (SLI) and identified a functional, SLI-associated variant affecting gene regulation in cells and post-mortem human brain. This variant and the affected gene (ARHGEF39) represent new putative risk factors for SLI. Furthermore, we identified 3'UTR regulatory variants across autism, schizophrenia and bipolar disorder NGS cohorts demonstrating their impact on neurodevelopmental and neuropsychiatric disorders. Our findings show the importance of investigating non-coding regulatory variants when determining risk factors contributing to neurodevelopmental and neuropsychiatric disorders. In the future, integration of such regulatory variation with protein coding changes will be essential for uncovering the genetic causes of complex neurological disorders and the fundamental mechanisms underlying health and disease.

Localized axillary milia en plaque: a rare cutaneous case presentation of systemic amyloidosis.

Systemic AL amyloidosis is known to be associated with plasma cell dyscrasias, including multiple myeloma. The cutaneous manifestations of systemic AL amyloidosis are varied, but typically include waxy plaques or subcutaneous nodules. We report a woman who presented with bilateral eruptions of hyperpigmented plaques in her axillae, which were diagnosed as milia en plaque. She had a history of multiple myeloma, for which she was under the care of a haematologist. This is the first documented case, to our knowledge, of an eruption in the axillae being milia en plaque.

Multipoint genome-wide linkage scan for nonword repetition in a multigenerational family further supports chromosome 13q as a locus for verbal trait disorders.

Verbal trait disorders encompass a wide range of conditions and are marked by deficits in five domains that impair a person's ability to communicate: speech, language, reading, spelling, and writing. Nonword repetition is a robust endophenotype for verbal trait disorders that is sensitive to cognitive processes critical to verbal development, including auditory processing, phonological working memory, and motor planning and programming. In the present study, we present a six-generation extended pedigree with a history of verbal trait disorders. Using genome-wide multipoint variance component linkage analysis of nonword repetition, we identified a region spanning chromosome 13q14-q21 with LOD = 4.45 between 52 and 55 cM, spanning approximately 5.5 Mb on chromosome 13. This region overlaps with SLI3, a locus implicated in reading disability in families with a history of specific language impairment. Our study of a large multigenerational family with verbal trait disorders further implicates the SLI3 region in verbal trait disorders. Future studies will further refine the specific causal genetic factors in this locus on chromosome 13q that contribute to language traits.

Maintenance rituximab after autologous stem cell transplantation in patients with mantle cell lymphoma.

BACKGROUND: High-dose therapy and autologous stem cell transplantation (ASCT) improves outcomes for patients with mantle cell lymphoma (MCL), but relapse ultimately occurs in most patients. Recently presented interim results from a phase III prospective trial suggest maintenance rituximab (MR) after ASCT for MCL improves progression-free survival (PFS). The maturation of these data and any benefit of MR on overall survival (OS) remain to be defined. PATIENTS AND METHODS: In this retrospective study, we examined a cohort of consecutive patients with MCL that underwent ASCT for MCL at our center and evaluated their outcomes according to whether they received MR after ASCT (n = 50) or did not (n = 107). MR was treated as a time-dependent covariate to account for variation in timing of its initiation. RESULTS: MR was associated with an improved PFS [hazard ratio (HR) 0.44; confidence interval (CI) (0.24-0.80), P = 0.007] and overall survival (OS; HR 0.46; CI 0.23-0.93, P = 0.03) following a multivariate adjustment for confounding factors with a median follow-up of ∼5 years. Grade 4 neutropenia was increased (34% versus 18%, P = 0.04) in the MR group, but no effect on the rate of mortality unrelated to relapse was observed. CONCLUSIONS: These data support that MR after ASCT for MCL confers a benefit in PFS and additionally suggest it may improve OS. General application of this strategy will require confirmation of benefit in prospective randomized trials.

Mapping water uptake in organic coatings using AFM-IR.

The long-term failure of seemingly intact corrosion resistant organic coatings is thought to occur via the development of ionic transport channels, which spontaneously evolve from hydrophilic regions on immersion, i.e., as a result of localized water uptake. To this end, we investigate water uptake characteristics for industrial epoxy-phenolic can coatings after immersion in deionized water and drying. Moisture sorption and the changing nature of polymer-water interactions are assessed using FTIR for dry and pre-soaked films. More water is found to be absorbed by the pre-soaked coatings on exposure to a humid environment, with a greater degree of hydrogen-bonding between the polymer and water. Furthermore, morphological changes are then correlated to localized water uptake using the AFM-IR technique. Nanoscale softened regions develop on soaking, and these are found to absorb a greater proportion of water from a humid environment.

The DYX2 locus and neurochemical signaling genes contribute to speech sound disorder and related neurocognitive domains.

A major milestone of child development is the acquisition and use of speech and language. Communication disorders, including speech sound disorder (SSD), can impair a child's academic, social and behavioral development. Speech sound disorder is a complex, polygenic trait with a substantial genetic component. However, specific genes that contribute to SSD remain largely unknown. To identify associated genes, we assessed the association of the DYX2 dyslexia risk locus and markers in neurochemical signaling genes (e.g., nicotinic and dopaminergic) with SSD and related endophenotypes. We first performed separate primary associations in two independent samples - Cleveland SSD (210 affected and 257 unaffected individuals in 127 families) and Denver SSD (113 affected individuals and 106 unaffected individuals in 85 families) - and then combined results by meta-analysis. DYX2 markers, specifically those in the 3' untranslated region of DCDC2 (P = 1.43 × 10(-4) ), showed the strongest associations with phonological awareness. We also observed suggestive associations of dopaminergic-related genes ANKK1 (P = 1.02 × 10(-2) ) and DRD2 (P = 9.22 × 10(-3) ) and nicotinic-related genes CHRNA3 (P = 2.51 × 10(-3) ) and BDNF (P = 8.14 × 10(-3) ) with case-control status and articulation. Our results further implicate variation in putative regulatory regions in the DYX2 locus, particularly in DCDC2, influencing language and cognitive traits. The results also support previous studies implicating variation in dopaminergic and nicotinic neural signaling influencing human communication and cognitive development. Our findings expand the literature showing genetic factors (e.g., DYX2) contributing to multiple related, yet distinct neurocognitive domains (e.g., dyslexia, language impairment, and SSD). How these factors interactively yield different neurocognitive and language-related outcomes remains to be elucidated.