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Anshul Shah,1 Jonathan C Tosh,2 Apoorva Ambavane,2 Andreas Nikolaou,2 Cosmina Hogea,3 Yevgeniy Samyshkin,4 Boris Gorsh,3 Eric M Maiese,5 Feng Wang3 1Modelling and Simulation, Evidera, Waltham, MA, USA; 2Modelling and Simulation, Evidera, London, UK; 3Value Evidence and Outcomes, GlaxoSmithKline, Upper Providence, PA, USA; 4Value Evidence and Outcomes, GlaxoSmithKline, Brentford, UK; 5Value Evidence and Outcomes, GlaxoSmithKline, Philadelphia, PA, USACorrespondence: Anshul ShahEvidera, 500 Totten Pond Road, Suite 500, Waltham, MA, 02451, USATel +1 781 640 8941Email Anshul.shah@evidera.comPurpose: Estimate the budget impact of belantamab mafodotin (belamaf) for patients with relapsed/refractory multiple myeloma (RRMM) who have received ≥ 4 prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.Methods: A budget impact analysis (BIA) was developed to estimate the cost difference between current (no belamaf) and projected (with belamaf) market scenarios over 3 years. Comparators were identified from a systematic literature review and included selinexor + dexamethasone or best supportive care. The number of treatment-eligible patients were estimated using an epidemiology model. Base-case analyses were conducted from a US commercial payer perspective (cost year: 2019). Model inputs included market share estimates, treatment duration, and costs of drug acquisition/administration, concomitant medications, adverse event (AE) management, treatment monitoring, and subsequent treatments based on published literature/cost databases. Budget impact, calculated as the difference in costs between current and projected scenarios over 3 years, was reported as cost per member per month (PMPM) and per member per year (PMPY). One-way sensitivity analysis assessed which key parameters most affected model outcomes. Alternative scenarios were tested (1- or 5-year time horizon; Medicare perspective; negligible cost of mental status change AE).Results: In a hypothetical commercial payer health plan with 1 million members, 33 patients were identified as treatment-eligible over 3 years. Introducing belamaf for patients with RRMM resulted in an estimated budget-neutral PMPM cost of −

Summary: An assumption in aquaculture of Atlantic salmon is that male and female growth within families is perfectly genetically correlated. That is, families would rank identically if based on male growth only or female growth only. Also, growth in freshwater and sea water is assumed to be highly correlated between males and females within families. However, structural analysis of the DNA of Atlantic salmon has found that the linkage maps of females differ significantly from that of males. Genetic variability for any trait measured on females could be greater or lesser than on males. Thus, male and female growth might be considered as separate traits giving rise to families ranking differently depending on gender. A multiple trait family model for weight and length at 3 years of age in Atlantic salmon according to gender was applied to data on North American Atlantic salmon obtained from the Oak Bay Hatchery in New Brunswick, Canada. Genetic correlations between male and female growth in both freshwater and sea water were estimated by Bayesian methods. The estimates support the possible existence of gender dimorphism in North American Atlantic salmon for growth traits. [ABSTRACT FROM AUTHOR]

Abstract: Our objective was to detect single nucleotide polymorphisms (SNPs) associated with resistance to the salmon louse in the Saint John River aquacultural population of North American Atlantic salmon using estimated breeding values (EBVs) and 6K genotypes from the parent‐generation and lice count phenotypes from the challenged, but ungenotyped, offspring‐generation. In 2011 and 2012, we challenged recent smolts with approximately 100 copepodids each. Fish were euthanized once the lice reached the chalimus stages and lice count, sex, tank and salt water weight were recorded. We used a multiple trait model to estimate breeding values for the parent‐generation using their own fresh water weights and the salt water weights and lice counts of the offspring‐generation. Salmon lice count heritability for untransformed and transformed data was 0.17 and 0.29 respectively. Two different genome‐wide association study methods were compared: (i) forward multiple linear regression and (ii) a mixed linear model using principal components to correct for population stratification as implemented in the egscore function of GenABEL. The two methods detected different SNPs located on different chromosomes. The multiple regression method incorporated 70 SNPs found on chromosomes 2, 7, 9, 12, 14, 15, 21, 22, 1p/23, 24. Many SNPs entered into the forward multiple regression are likely to be false positives from not correcting for the observed population stratification and cryptic relatedness. In contrast, the mixed linear model identified only two SNPs, one on chromosome 1p/23 (6.9%) and one on chromosome 1q (6.1%) consistent with louse‐resistance being a quantitative trait. [ABSTRACT FROM AUTHOR]

The article examines the cost effectiveness of a pragmatic exercise intervention (EXIMS) in multiple sclerosis (MS) patients. Although, exercise is a safe, non-pharmacological adjunctive treatment for MS patients, cost effective approaches within health care settings are needed. A total of 120 MS patients were included in the study.

The article examines that the effects of a practically implemented exercise programme on self-directed exercise behavior. It also assesses vital health outcomes in people with multiple sclerosis (PwMS) to nine months of follow-up. 120 PwMS were included in the study who underwent a parallel-arm, randomized controlled trial.

Variance components were estimated for 2 body size traits of Atlantic cod at 2 time points. Wild-caught founders from 3 regions off eastern North America were spawned and their progeny were reared at 2 locations in 2 consecutive years. Full-sib families (n = 148) were kept separate until individuals achieved a size large enough to be tagged. At that time (220 d of age), BW and length of 47,637 offspring from 90 sires and 89 dams were recorded. The juveniles were then transferred to sea cages at 3 sites, where they grew further for more than a year. A second set of measurements was collected on 11,839 fish (634 d of age). Dispersion parameters were estimated using REML in bivariate analyses. Models included fixed degree-days (covariate), year x location subclasses, and genetic groups composed of connected families within region of origin. Random factors were animal (additive genetic effects), considering known relationships among the fish; dam (maternal effects); and family (effects common to full-sibs). At tagging, heritability estimates were small to moderate (0.15 and 0.24 for BW and length, respectively; SE = 0.14), similar to or somewhat larger than the proportions of variation ascribed to dams and families (11 to 16%). Later, heritability estimates were greater (0.27 ± 0.08 and 0.31 ± 0.09 for BW and length, respectively), whereas darn and family variance proportions were very small (3 to 4%). Omitting maternal or family components substantially increased the values obtained for heritability at both time points. At the later point, failure to account for maternal effects inflated heritability estimates by about 24% for both traits; ignoring family effects had double the impact. These effects persisted even though endogenous feeding lasts only a couple of weeks in this species and the fish had been pooled since tagging. Discarding data from parents that were completely confounded with their mates decreased heritability estimates slightly (by 0.04, for both traits) at the second point, with no loss of precision despite 15% fewer records and 34% fewer parents; the improved design seemed to have more fully disentangled the additive genetic effects. Estimates of genetic correlations between traits and between time points were very large (>0.89). The results imply that genetic variation exists for body size of cod at both stages. Poor data structure and inadequate models can potentially lead to overstatement of heritability, and thus also of the predicted selection response. [ABSTRACT FROM AUTHOR]

Presents a study which evaluated the influence of three production systems (intensive, extensive, and intermediate) on litter size, lamb growth, and carcass characteristics in sheep. Materials and methods; Results and discussion; Implications.

Presents a letter to the editor in response to the article "Clozapine-Induced Toxic Hepatitis with Skin Rash," by S. Y. Y. Fong, K. L. Au Yeung, J. M. Y. Tosh and Y. K. Wing in the January 2005 issue of "Journal of Psychopharmacology."

Abstract: Exercise is an effective intervention for improving function, mobility and health-related quality of life in people with multiple sclerosis (PwMS). Questions remain however, regarding the effectiveness of pragmatic exercise interventions for evoking tangible and sustained increases in physical activity and long-term impact on important health outcomes in PwMS. Furthermore, dose–response relationships between exercise and health outcomes have not previously been reported in PwMS. These issues, and improved knowledge of cost effectiveness, are likely to influence key decisions of health policy makers regarding the implementation of exercise therapy as part of the patient care pathway for PwMS. Hence, the primary aim of this study is to investigate whether a 12-week tapered programme of supervised exercise, incorporating cognitive-behavioural techniques to facilitate sustained behaviour change, is effective for evoking improvements in physical activity and key health outcomes in PwMS over 9months of follow-up. A total of 120 PwMS will be randomised (1:1) to either a 12-week pragmatic exercise therapy intervention or usual care control group. Participants will be included on the basis of a clinical diagnosis of MS, with an expanded disability status score (EDSS) between 1 and 6.5. Outcome measures, to be assessed before and after the intervention and 6months later, will include physical activity, clinical and functional measures and health-related quality of life. In addition, the cost effectiveness of the intervention will be evaluated and dose–response relationships between physical activity and the primary/secondary outcomes in those with mild and more severe disease will be explored. [Copyright &y& Elsevier]

Qualitative interviews were conducted with nine individuals identifying as LGBTQ to identify recommendations for improving sexual and reproductive healthcare at a local clinic on the California Central Coast. Interviewees were recruited at local Pride events. Grounded theory methodology revealed several themes related to participants' desires for a LGBTQ-affirmative sexual and reproductive healthcare setting. Themes identified included: Beyond Enacted Inclusivity (avoiding a performative demonstration of LGBTQ-affirming care); Anti-Institutional Care (a political and visual challenge to what the healthcare setting should look like), a One-Stop-Shop (encompassing several types of care under one roof); Constrained Visibility (where LGBTQ identities are reflected but not exposed); and Community and Social Wellness (to be in community with other LGBTQ-serving organisations and one another in mutual support and celebration). Research implications and clinical recommendations are described at the local and system levels.

Objectives: From the US Medicare perspective, this study compared the cost-effectiveness of tepotinib and capmatinib for treating metastatic non-small cell lung cancer with tumors harboring mesenchymal-epithelial transition factor gene exon 14 skipping., Methods: A 3-state partitioned survival model assessed outcomes over a lifetime horizon. Parametric survival analysis of the phase 2 VISION trial informed clinical inputs for tepotinib. Capmatinib inputs were captured using hazard ratios derived from an unanchored matching-adjusted indirect comparison study and published literature. National cost databases, trial data, and literature furnished drug, treatment monitoring, and disease/adverse event management expenditures (2021 US dollars) and utility inputs. Outcomes were discounted at 3% annually., Results: In the base case, tepotinib dominated capmatinib in frontline settings (incremental discounted quality-adjusted life-years [QALYs] and costs of 0.2127 and -$47 756, respectively) while realizing an incremental cost-effectiveness ratio of $274 514/QALY in subsequent lines (incremental QALYs and costs of 0.3330 and $91 401, respectively). In a line agnostic context, tepotinib produced an incremental cost-effectiveness ratio of $105 383/QALY (incremental QALYs and costs of 0.2794 and $29 447, respectively). Sensitivity and scenarios analyses for individual lines typically supported the base case, whereas those for the line agnostic setting suggested sensitivity to drug acquisition costs and efficacy inputs., Conclusions: Tepotinib could be cost-effective versus capmatinib in frontline and line agnostic contexts, considering the range of willingness-to-pay thresholds recommended by the Institute for Clinical and Economic Review ($100 000-$150 000/QALY). Tepotinib could be cost-effective in subsequent lines at higher willingness-to-pay levels. These results are to be interpreted cautiously, considering uncertainty in key model inputs., (Copyright © 2023. Published by Elsevier Inc.)

Individuals who have Down syndrome (DS) frequently develop early onset Alzheimer's disease (AD), a neurodegenerative condition caused by the buildup of aggregated amyloid-β (Aβ) and tau proteins in the brain. Aβ is produced by amyloid precursor protein ( APP ), a gene located on chromosome 21. People who have DS have three copies of chromosome 21 and thus also an additional copy of APP ; this genetic change drives the early development of AD in these individuals. Here we use a combination of next-generation mouse models of DS (Tc1, Dp3Tyb, Dp(10)2Yey and Dp(17)3Yey) and a knockin mouse model of Aβ accumulation ( App NL-F ) to determine how chromosome 21 genes, other than APP , modulate APP/Aβ in the brain when in three copies. Using both male and female mice, we demonstrate that three copies of other chromosome 21 genes are sufficient to partially ameliorate Aβ accumulation in the brain. We go on to identify a subregion of chromosome 21 that contains the gene(s) causing this decrease in Aβ accumulation and investigate the role of two lead candidate genes, Dyrk1a and Bace2 Thus, an additional copy of chromosome 21 genes, other than APP , can modulate APP/Aβ in the brain under physiological conditions. This work provides critical mechanistic insight into the development of disease and an explanation for the typically later age of onset of dementia in people who have AD in DS, compared with those who have familial AD caused by triplication of APP SIGNIFICANCE STATEMENT Trisomy of chromosome 21 is a commonly occurring genetic risk factor for early-onset Alzheimer's disease (AD), which has been previously attributed to people with Down syndrome having three copies of the amyloid precursor protein ( APP copy number (Wiseman et al., 2018; Tosh et al., 2021). Here, we use a mapping approach to narrow down the genetic cause of the modulation of pathology, demonstrating that gene(s) on chromosome 21 decrease Aβ accumulation in the brain, independently of alterations to full-length APP or C-terminal fragment abundance and that just 38 genes are sufficient to cause this.APP copy number (Wiseman et al., 2018; Tosh et al., 2021). Here, we use a mapping approach to narrow down the genetic cause of the modulation of pathology, demonstrating that gene(s) on chromosome 21 decrease Aβ accumulation in the brain, independently of alterations to full-length APP or C-terminal fragment abundance and that just 38 genes are sufficient to cause this., (Copyright © 2022 the authors.)

An organism or cell carrying a number of chromosomes that is not a multiple of the haploid count is in a state of aneuploidy. This condition results in significant changes in the level of expression of genes that are gained or lost from the aneuploid chromosome(s) and most cases in humans are not compatible with life. However, a few aneuploidies can lead to live births, typically associated with deleterious phenotypes. We do not understand why phenotypes arise from aneuploid syndromes in humans. Animal models have the potential to provide great insight, but less than a handful of mouse models of aneuploidy have been made, and no ideal system exists in which to study the effects of aneuploidy per se versus those of raised gene dosage. Here, we give an overview of human aneuploid syndromes, the effects on physiology of having an altered number of chromosomes and we present the currently available mouse models of aneuploidy, focusing on models of trisomy 21 (which causes Down syndrome) because this is the most common, and therefore, the most studied autosomal aneuploidy. Finally, we discuss the potential role of carrying an extra chromosome on aneuploid phenotypes, independent of changes in gene dosage, and methods by which this could be investigated further., (© 2021. The Author(s).)

Background: Patients with relapsed/refractory multiple myeloma (RRMM) require several lines of therapy, with typically shorter remission duration with each additional line., Research Design and Methods: The cost-effectiveness of belantamab mafodotin (belamaf; DREAMM-2; NCT03525678) was compared with selinexor plus dexamethasone (SEL+DEX; STORM Part 2; NCT02336815) among patients with RRMM who have received at least four prior therapies. The base case used a US commercial payer's perspective over a 10-year time horizon. Efficacy data were based on parametric survival analysis of DREAMM-2 and matching-adjusted indirect treatment comparison between DREAMM-2 and STORM Part 2, which assessed relative treatment effects between belamaf and SEL+DEX. Cost inputs included drug treatment, concomitant medications, adverse event management, subsequent treatments, and disease management., Results: Belamaf decreased total treatment costs per patient by $14,267 and increased patient life years by 0.74 and quality-adjusted life years (QALYs) by 0.49 versus SEL+DEX. Patients receiving belamaf accrued 0.12 fewer progression-free life years versus patients on SEL+DEX., Conclusions: From a US commercial payer's perspective, belamaf had lower costs, and increased QALYs and life-year gain, compared with SEL+DEX. Belamaf is therefore likely to be a cost-effective treatment option for patients with RRMM who have received four or more prior lines of therapy.

Down syndrome (DS), trisomy 21, results in many complex phenotypes including cognitive deficits, heart defects and craniofacial alterations. Phenotypes arise from an extra copy of human chromosome 21 (Hsa21) genes. However, these dosage-sensitive causative genes remain unknown. Animal models enable identification of genes and pathological mechanisms. The Dp1Tyb mouse model of DS has an extra copy of 63% of Hsa21-orthologous mouse genes. In order to establish whether this model recapitulates DS phenotypes, we comprehensively phenotyped Dp1Tyb mice using 28 tests of different physiological systems and found that 468 out of 1800 parameters were significantly altered. We show that Dp1Tyb mice have wide-ranging DS-like phenotypes, including aberrant erythropoiesis and megakaryopoiesis, reduced bone density, craniofacial changes, altered cardiac function, a pre-diabetic state, and deficits in memory, locomotion, hearing and sleep. Thus, Dp1Tyb mice are an excellent model for investigating complex DS phenotype-genotype relationships for this common disorder., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)

Aims: To estimate the budget impact of adding tepotinib to United States (US) health plans for treating adult patients with metastatic non-small cell lung cancer (mNSCLC) harboring mesenchymal-epithelial transition exon 14 ( MET ex14) skipping alterations., Methods: The base-case analysis was conducted from the perspective of a hypothetical Medicare plan of 1 million members. Scenarios were analysed for other US health plans. Treatments included tepotinib, capmatinib, crizotinib, and standard of care (SoC). Patients eligible for tepotinib were estimated from published epidemiological data and literature, and real-world evidence. Clinical inputs were derived from the phase II VISION trial, US prescribing information, and published literature. Tepotinib uptake and projected testing rates for MET ex14 skipping alterations were based on market research. Unit costs (2020 US dollars (USD)) and resource utilization associated with drug acquisition and administration, treatment monitoring, disease and adverse event (AE) management, and subsequent treatment were derived primarily from public sources., Results: In the base-case, 38-65 patients were eligible for tepotinib each year over the three-year time horizon. The cumulative net budgetary impact of tepotinib was -$692,541 (-2.6%); $26,531,670 in the scenario without tepotinib and $25,839,129 in the scenario with tepotinib. A negligible net budget impact was observed per member per month (PMPM) at $0.2457 and $0.2393, respectively, before and after tepotinib's introduction. Results were most sensitive to variability in unit costs of capmatinib and tepotinib and their corresponding median treatment durations. Sensitivity and scenario analyses support the conclusion that introducing tepotinib will have minimal budgetary impact for Medicare health plans. Similar results were obtained for other US health plans., Limitations: Assumptions and expert opinion were applied to address data gaps in key model inputs., Conclusions: The estimated budgetary impact of tepotinib for the treatment of adult patients with mNSCLC harboring MET ex14 skipping alterations is minimal from the perspective of US health plans.