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Oralee J Varnado,1 Tania Gulati,2 Anthony Wheeler,3 Margaret Hoyt1 1Value Evidence Outcomes – Research & Neuroscience, Indianapolis, IN, USA; 2Value Evidence Outcomes, Real World Evidence, Eli Lilly Services India, Private Limited, Bengaluru, Karnataka, India; 3Value Evidence Outcomes – Outcomes Liaisons, Indianapolis, IN, USACorrespondence: Oralee J Varnado, Value Evidence Outcomes – Research & Neuroscience, Lilly Corporate Center, Indianapolis, IN, 46285, USA, Email varnado_oralee_johnson@lilly.comPurpose: To describe treatment patterns, all-cause and migraine-related healthcare resource utilization (HCRU), and direct costs among people with migraine treated with concomitant calcitonin gene-related peptide monoclonal antibody (CGRP mAb) and novel acute migraine medications (ubrogepant, rimegepant, lasmiditan) in the United States (US).Patients and Methods: This retrospective, observational cohort study utilized data from the IBM MarketScan® Research Databases and included adults initiating CGRP mAb or novel acute migraine medication as index medications between May 01, 2018, and Feb 28, 2021. All-cause and migraine-related HCRU (number of visits) and costs at baseline (12 months pre-index) and at follow-up (12 months post-index) were descriptively analyzed; differences between values at follow-up and baseline were reported.Results: Of 4,167 included in the analysis (mean [SD] age: 43.7 [11.2] years), 89.2% were women, and 59.7% had chronic migraine. Adherence to the indexed CGRP mAb was 47% (using proportion of days covered [PDC]) and 80.1% (using medication possession ratio [MPR]); mean (SD) persistence was 273.4 (115.3) days). At follow-up, 43.9% of the patients discontinued their index preventive medication of which 80.2% switched to a different preventive migraine medication; 17.0% restarted their index preventive medication. Reductions in all-cause inpatient HCRU, all-cause inpatient and outpatient costs, and migraine-related outpatient HCRU were observed at follow-up vs. baseline, whereas increases in all-cause outpatient HCRU, all-cause medication costs, migraine-related inpatient HCRU, and migraine-related inpatient, outpatient, and medication costs were observed.Conclusion: In this study, observed treatment patterns with the indexed CGRP mAb were consistent with prior reports. Concomitant treatment with CGRP mAb and novel acute migraine medications led to reductions in some outcomes of HCRU and direct costs, however, increases were also observed. Treatment utilization, reductions in HCRU and cost savings identified in this study in favor of concomitant CGRP mAb and novel acute medications may help clinicians and other healthcare decision makers assessing appropriate therapeutic options for migraine management.Plain Language Summary: What was known before?The American Headache Society recommends concomitant use of preventive and acute medications for migraine.Data on treatment outcomes, and healthcare resource utilization (HCRU) and medical costs are limited for patients with migraine who use preventive and acute migraine medications concomitantly.What does this study add?Patients with migraine started treatment with preventive medications – calcitonin gene-related peptide monoclonal antibodies [CGRP mAb] such as galcanezumab/fremanezumab followed by newer acute medications (ubrogepant, rimegepant, and lasmiditan).About half the patients who started their migraine treatment with CGRP mAb continued to use the same medication after 1-year on treatment.Of those patients who stopped their initial CGRP mAb medication, most switched to other preventive migraine medications such as antiepileptics and beta blockers.Patients taking CGRP mAb and newer acute migraine medications had fewer overall inpatient healthcare visits but a higher number of overall outpatient healthcare visits and lower overall inpatient and outpatient costs after 1-year of follow-up.InterpretationIncreases in healthcare costs for migraine treatment over a 1-year period were observed in patients who used CGRP mAb and newer acute migraine medications.At follow-up, greater cost savings were seen for non-migraine treatment utilization and some migraine-related healthcare utilization in concomitant CGRP mAb and newer acute medication users.This study may help healthcare providers and payors to better understand how patients who use acute and preventive treatments for migraine perform after one year of their initial treatment. This may inform them to make informed decisions on long-term treatment for patients with migraine.Keywords: migraine, CGRP mAb, adherence, persistence, cost savings

In this work, we introduce a pair of multiobjective second-order symmetric dual variational problems. Weak, strong, and converse duality theorems for this pair are established under the assumption of r/-bonvexity/r/-pseudobonvexity. At the end, the static case of our problems has also been discussed. [ABSTRACT FROM AUTHOR]

The present investigation was concerned with the delayed discrete S-shaped software reliability growth model with imperfect debugging. In this paper, we developed a discrete model based on non-homogeneous Poisson process by considering two types of fault removal processes. Optimal release policy was suggested to predict the optimal test run after which the software should be released. The sensitivity analysis was performed on the cost and reliability functions. We used the adaptive neuro fuzzy inference system approach to facilitate the computational results and compared it with the analytical results. [ABSTRACT FROM AUTHOR]

The aim of the present work is to obtain effective permittivity of the reaction mixture during esterification reactions that can be used in a dynamic simulation environment and analysis the dielectric properties during the reaction process. Microwave heating serves as an excellent tool for carrying out such reactions and the multiphysics simulations need effective permittivity as one of the most important inputs. In this work, we perform the esterification reaction between ethanol, acetic acid and butyric acid using a temperature cycle in order to measure the effective permittivity of the reaction mixture. The obtained result is fitted using a bivariate function of the concentration of one of the products of the reaction and temperature of the mixture. The computed results show good agreement with measured values with maximum errors for the synthesis reactions of ethyl butyrate and ethyl acetate being 4.94% and 3.68%, respectively. [ABSTRACT FROM AUTHOR]

In this paper, we establish weak and strong duality theorems for a pair of multi-objective symmetric dual problems. This removes several omissions in the paper "Symmetric and self duality in vector optimization problem, Applied Mathematics and Computation 183 (2006) 1121-1126". [ABSTRACT FROM AUTHOR]

In this paper we introduce the concept of higher-order (F, α, β ρ, d)-convexity with respect to a differentiable function K. Based on this generalized convexity, sufficient optimality conditions for a nonlinear programming problem (NP) are obtained. Duality relations for Mond-Weir and Wolfe duals of (NP) have also been discussed. These duality results are then applied to nonlinear fractional programming problems. [ABSTRACT FROM AUTHOR]

In this work, we first modify a converse duality theorem for second-order dual of a scalar variational problem. We then consider its multiobjective analogue and obtain necessary optimality conditions and duality relations. At the end, the static case of our problems has also been discussed. [ABSTRACT FROM AUTHOR]

In this paper, a nondifferentiable multiobjective programming problem is considered where every component of objective and constraint functions contain a term involving the support function of a compact convex set. A new class of higher order ( F, α, ρ, d)-type I function is introduced. Necessary optimality conditions and the duality theorems for Wolfe and unified higher order dual problems are established. Several known results can be deduced as special cases. [ABSTRACT FROM AUTHOR]

In this paper, a new class of second-order (F, α, ρ, d)-V-type I functions is introduced that generalizes the notion of (F, α, ρ, θ)-V-convex functions introduced by Zalmai (Computers Math. Appl. 2002; 43:1489-1520) and (F, α, ρ, p, d)-type I functions defined by Hachimi and Aghezzaf (Numer. Funct. Anal. Optim. 2004; 25:725-736). Based on these functions, weak, strong, and strict converse duality theorems are derived for Wolfe and Mond-Weir type multiobjective dual programs in order to relate the efficient and weak efficient solutions of primal and dual problems. [ABSTRACT FROM AUTHOR]

A pair of nondifferentiable mixed symmetric dual programming problems is introduced and duality theorems are proved. This unifies two existing formulations of symmetric dual problems appeared in the literature. [ABSTRACT FROM AUTHOR]

Two distinct pairs of secound order symmetric dual programs are considered and appropriate duality theorems are established under η-convexity/η-concavity and η-pseudoconvexity η-psecoudoconcavity of the kernel function K(x,y). Assuming the additional hypothesis of skew symmetry for K(x,y) these programs are shown to be self dual. Also, it is observed that for a particular kernel function, both these pairs are reduced to the general nonlinear problem and its Wolfe type secound order dual introduced by Mangasarian. [ABSTRACT FROM AUTHOR]

Sleep spindles appear to play an important role in learning new motor skills. Motor skill learning engages several brain regions with two important areas being the motor cortex (M1) and the cerebellum (CB). However, the neurophysiological processes in these areas during sleep, especially how spindle oscillations affect local and cross-region spiking, are not fully understood. We recorded an activity from the M1 and cerebellar cortex in eight rats during spontaneous activity to investigate how sleep spindles in these regions are related to local spiking as well as cross-region spiking. We found that M1 firing was significantly changed during both M1 and CB spindles, and this spiking occurred at a preferred phase of the spindle. On average, M1 and CB neurons showed most spiking at the M1 or CB spindle peaks. These neurons also developed a preferential phase locking to local or cross-area spindles with the greatest phase-locking value at spindle peaks; however, this preferential phase locking was not significant for cerebellar neurons when compared with CB spindles. Additionally, we found that the percentage of task-modulated cells in the M1 and CB that fired with nonuniform spike phase distribution during M1/CB spindle peaks were greater in the rats that learned a reach-to-grasp motor task robustly. Finally, we found that spindle band LFP coherence (for M1 and CB LFPs) showed a positive correlation with success rate in the motor task. These findings support the idea that sleep spindles in both the M1 and CB recruit neurons that participate in the awake task to support motor memory consolidation., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Fleischer et al.)

Temporally coordinated neural activity is central to nervous system function and purposeful behavior. Still, there is a paucity of evidence demonstrating how this coordinated activity within cortical and subcortical regions governs behavior. We investigated this between the primary motor (M1) and contralateral cerebellar cortex as rats learned a neuroprosthetic/brain-machine interface (BMI) task. In neuroprosthetic task, actuator movements are causally linked to M1 "direct" neurons that drive the decoder for successful task execution. However, it is unknown how task-related M1 activity interacts with the cerebellum. We observed a notable 3 to 6 hertz coherence that emerged between these regions' local field potentials (LFPs) with learning that also modulated task-related spiking. We identified robust task-related indirect modulation in the cerebellum, which developed a preferential relationship with M1 task-related activity. Inhibiting cerebellar cortical and deep nuclei activity through optogenetics led to performance impairments in M1-driven neuroprosthetic control. Together, these results demonstrate that cerebellar influence is necessary for M1-driven neuroprosthetic control.

Background: Calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) are recommended by the United Kingdom National Institute of Health and Care Excellence for the prevention of migraine as treatment beyond third line. We report migraine prevalence and preventive treatment patterns in the adult United Kingdom primary care population over a 7.5-year period, focusing on patients ceasing ≥ 3 oral preventive medication classes., Methods: Study populations were retrieved from the Clinical Practice Research Datalink GOLD database (study period: 19 September 2012 to 1 January 2020; inclusion criteria: ≥12 months follow-up, current-in-dataset, adult on 1 January 2020). Patients who used ≥ 1 oral preventive medication with ≥ 3-year follow-up after first prescription were considered preventive treatment users; class cessation was defined as cessation without evidence of restart within 6 months from end-of-supply date., Results: On 1 January 2020, 3.0% of the total study population were diagnosed with migraine (n = 81,190/2,664,306); of these, 42.4% were preventive treatment users (n = 34,448/81,190). The most frequently used oral migraine preventive medication classes were beta-blockers (n = 14,713), tricyclic antidepressants (n = 14,415) and antiepileptics (n = 6497). Among preventive treatment users, 7.7% (n = 2653/34,448) ceased ≥ 3 oral preventive medication classes; of these, 21.7% (n = 576/2653) had been referred to a neurologist., Conclusions: Compared to existing population-based estimates of migraine prevalence, our data further corroborates that a considerable proportion of patients with migraine do not seek treatment. Among those who sought primary care within a 7.5-year period, almost half received empirical oral preventive treatment. Importantly, nearly 1 of 10 preventive treatment users ceased ≥ 3 oral preventive medication classes, highlighting a need for additional therapeutic options. These patients may benefit from CGRP antagonists and/or injectable onabotulinumtoxinA; however, only a minority was referred to specialist care, where these options would be more available., Trial Registration: Not applicable., (© 2024. The Author(s).)

Sleep is known to promote recovery post-stroke. However, there is a paucity of data profiling sleep oscillations in the post-stroke human brain. Recent rodent work showed that resurgence of physiologic spindles coupled to sleep slow oscillations (SOs) and concomitant decrease in pathological delta ( δ ) waves is associated with sustained motor performance gains during stroke recovery. The goal of this study was to evaluate bilaterality of non-rapid eye movement (NREM) sleep-oscillations (namely SOs, δ -waves, spindles, and their nesting) in post-stroke patients vs. healthy control subjects. We analyzed NREM-marked electroencephalography (EEG) data in hospitalized stroke-patients ( n  = 5) and healthy subjects ( n  = 3). We used a laterality index to evaluate symmetry of NREM oscillations across hemispheres. We found that stroke subjects had pronounced asymmetry in the oscillations, with a predominance of SOs, δ -waves, spindles, and nested spindles in affected hemisphere, when compared to the healthy subjects. Recent preclinical work classified SO-nested spindles as restorative post-stroke and δ -wave-nested spindles as pathological. We found that the ratio of SO-nested spindles laterality index to δ -wave-nested spindles laterality index was lower in stroke subjects. Using linear mixed models (which included random effects of concurrent pharmacologic drugs), we found large and medium effect size for δ -wave nested spindle and SO-nested spindle, respectively. Our results in this pilot study indicate that considering laterality index of NREM oscillations might be a useful metric for assessing recovery post-stroke and that factoring in pharmacologic drugs may be important when targeting sleep modulation for neurorehabilitation post-stroke., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Simpson, Rangwani, Abbasi, Chung, Reed and Gulati.)

Objectives: To describe selected baseline characteristics, continuation with baricitinib and disease activity over time in patients initiating treatment with baricitinib in a UK real-world rheumatology setting., Methods: Baseline and follow-up data were analysed from baricitinib-treated patients newly recruited to the British Society for Rheumatology Biologics Registry-RA (BSRBR-RA) baricitinib cohort between 1 January 2018 and 31 March 2020. The primary objective was to evaluate continuation of baricitinib treatment in patients with at least one follow-up. Analyses were performed using the full baricitinib cohort, overall and by patient subgroup: biologic DMARD (bDMARD)/targeted synthetic (ts)DMARD-naive vs -experienced, baricitinib 4 vs 2 mg, age ≥65 vs <65 years, monotherapy vs combination therapy and male vs female., Results: At baseline, the study cohort (n = 561) was 76.5% female, mean age 60.0 years, had longstanding (mean 13.1 years) and severe RA, and 54.0% had previously received a bDMARD/tsDMARD. Of 265 and 110 patients completing the 6- and 12-month follow-ups with available data, 77.7 and 69.1% remained on baricitinib at each time, respectively. In all Kaplan-Meier analyses, >60% of patients remained on baricitinib at 540 days. Continuation of baricitinib therapy differed between some subgroup pairs (bDMARD/tsDMARD naive/experienced, baricitinib 2 mg/4 mg). Disease activity was lower at both follow-ups than at baseline, overall and in all subgroups., Conclusion: In the early years of real-world baricitinib use in the UK, a high proportion of patients continued with treatment at both 6 and 12 months, at which times disease activity was lower than at baseline., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Peptide receptor radionuclide therapy (PRRT) using 177 Lutetium-DOTA-octreotate (LuTate) for neuroendocrine tumours (NET) is now an approved treatment available in many countries, though primary or secondary resistance continue to limit its effectiveness or durability. We hypothesised that a genome-wide CRISPR/Cas9 screen would identify key mediators of response to LuTate and gene targets that might offer opportunities for novel combination therapies for NET patients. Methods: We utilised a genome-wide CRISPR-Cas9 screen in LuTate-treated cells to identify genes that impact on the sensitivity or resistance of cells to LuTate. Hits were validated through single-gene knockout. LuTate-resistant cells were assessed to confirm LuTate uptake and retention, and persistence of somatostatin receptor 2 (SSTR2) expression. Gene knockouts conferring LuTate sensitivity were further characterised by pharmacological sensitisation using specific inhibitors and in vivo analysis of the efficacy of these inhibitors in combination with LuTate. Results: The CRISPR-Cas9 screen identified several potential targets for both resistance and sensitivity to PRRT. Two gene knockouts which conferred LuTate resistance in vitro , ARRB2 and MVP , have potential mechanisms related to LuTate binding and retention, and modulation of DNA-damage repair (DDR) pathways, respectively. The screen showed that sensitivity to LuTate treatment in vitro can be conferred by the loss of a variety of genes involved in DDR pathways, with loss of genes involved in Non-Homologous End-Joining (NHEJ) being the most lethal. Loss of the key NHEJ gene, PRKDC (DNA-PK), either by gene loss or inhibition by two different inhibitors, resulted in significantly reduced cell survival upon exposure of cells to LuTate. In SSTR2-positive xenograft-bearing mice, the combination of nedisertib (a DNA-PK specific inhibitor) and LuTate produced a more robust control of tumour growth and increased survival compared to LuTate alone. Conclusions: DDR pathways are critical for sensing and repairing radiation-induced DNA damage, and our study shows that regulation of DDR pathways may be involved in both resistance and sensitivity to PRRT. Additionally, the use of a DNA-PK inhibitor in combination with LuTate PRRT significantly improves the efficacy of the treatment in pre-clinical models, providing further evidence for the clinical efficacy of this combination., Competing Interests: Competing Interests: The authors have declared that no competing interest exists with respect to the current research. Outside this study RJH declares being shareholder in Telix Pharmaceuticals., (© The author(s).)

Introduction: Personal protective equipment (PPE) inhibits heat dissipation and elevates heat strain. Impaired cooling with PPE warrants investigation into practical strategies to improve work capacity and mitigate exertional heat illness., Purpose: Examine physiological and subjective effects of forearm immersion (FC), fan mist (MC), and passive cooling (PC) following three intermittent treadmill bouts while wearing PPE., Methods: Twelve males (27 ± 6 years; 57.6 ± 6.2 ml/kg/min; 78.3 ± 8.1 kg; 183.1 ± 7.2 cm) performed three 50-min (10 min of 40%, 70%, 40%, 60%, 50% vVO 2 max) treadmill bouts in the heat (36 °C, 30% relative humidity). Thirty minutes of cooling followed each bout, using one of the three strategies per trial. Rectal temperature (T core ), skin temperature (T sk ), heart rate (HR), heart rate recovery (HRR), rating of perceived exertion (RPE), thirst, thermal sensation (TS), and fatigue were obtained. Repeated-measures analysis of variance (condition x time) detected differences between interventions., Results: Final T core  was similar between trials (P > .05). Cooling rates were larger in FC and MC vs PC following bout one (P < .05). HRR was greatest in FC following bouts two (P = .013) and three (P < .001). T sk , fluid consumption, and sweat rate were similar between all trials (P > .05). TS and fatigue during bout three were lower in MC, despite similar T core  and HR., Conclusion: Utilizing FC and MC during intermittent work in the heat with PPE yields some thermoregulatory and cardiovascular benefit, but military health and safety personnel should explore new and novel strategies to mitigate risk and maximize performance under hot conditions while wearing PPE., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The motor cortex controls skilled arm movement by recruiting a variety of targets in the nervous system, and it is important to understand the emergent activity in these regions as refinement of a motor skill occurs. One fundamental projection of the motor cortex (M1) is to the cerebellum. However, the emergent activity in the motor cortex and the cerebellum that appears as a dexterous motor skill is consolidated is incompletely understood. Here, we report on low-frequency oscillatory (LFO) activity that emerges in cortico-cerebellar networks with learning the reach-to-grasp motor skill. We chronically recorded the motor and the cerebellar cortices in rats, which revealed the emergence of coordinated movement-related activity in the local-field potentials as the reaching skill consolidated. Interestingly, we found this emergent activity only in the rats that gained expertise in the task. We found that the local and cross-area spiking activity was coordinated with LFOs in proficient rats. Finally, we also found that these neural dynamics were more prominently expressed during accurate behavior in the M1. This work furthers our understanding on emergent dynamics in the cortico-cerebellar loop that underlie learning and execution of precise skilled movement., Competing Interests: The authors declare no competing financial interests., (Copyright © 2023 Fleischer et al.)

Objectives: The mental health of adolescent girls in countries of South Asia is related to several social and cultural factors including gender disadvantage, especially in low resource settings such as tribal areas. The coronavirus disease 2019 (COVID-19) pandemic has increased this vulnerability even further. This study assesses the association of gender disadvantage with psychological distress among adolescent girls residing in a tribal area of India and examines the role of resilience., Materials and Methods: The study was conducted during the COVID-19 pandemic first wave in 2020 using telephonic interviews with 102 girls aged 15-20 from one block (65.46% tribal population) of a predominantly tribal area in Central India. Trained interviewers administered translated versions of the Kessler Psychological Distress 10-item scale (K-10), the Checklist for Assessment of Gender Disadvantage (CAGED), and the Brief Resilience Scale (BRS). Pair-wise correlation was conducted between gender disadvantage, resilience and psychological distress using CAGED, BRS and K-10 scores. A one-way ANOVA was used to compare mean difference in CAGED domain scores and K-10 severity score groups., Results: The mean age of girls was 17.62 years (standard deviation 1.64). Scores on K-10 indicating moderate to severe psychological distress were seen among 27.5% of the respondents. Girls reported lack of space/privacy (39.2%), lack of freedom to pursue interests (32.4%), opinions not being considered (31.4%), and financial difficulties as hindrance to opportunities (28.4%) as common experiences of gender disadvantage. Gender disadvantage was directly associated with severity of psychological distress and inversely with resilience., Conclusion: This study indicates the importance of decreasing gender disadvantage for improving the mental health of young women and girls in underserved areas. The role of peer group interventions and engaging men and boys using gender transformative interventions in improving mental health needs to be studied., Competing Interests: There are no conflicts of interest., (© 2022 Published by Scientific Scholar on behalf of Journal of Neurosciences in Rural Practice.)

In this study, we extended our previously developed anatomically detailed three-dimensional (3-D) thermoregulatory virtual human model for predicting heat stress to allow for predictions of heat and cold stress in one unified model. Starting with the modified Pennes bioheat transfer equation to estimate the spatiotemporal temperature distribution within the body as the underlying modeling structure, we developed a new formulation to characterize the spatial variation of blood temperature between body elements and within the limbs. We also implemented the means to represent heat generated from shivering and skin blood flow that apply to air exposure and water immersion. Then, we performed simulations and validated the model predictions with experimental data from nine studies, representing a wide range of heat- and cold-stress conditions in air and water and physical activities. We observed excellent agreement between model predictions and measured data, with average root mean squared errors of 0.2°C for core temperature, 0.9°C for mean skin temperature, and 27 W for heat from shivering. We found that a spatially varying blood temperature profile within the limbs was crucial to accurately predict core body temperature changes during very cold exposures. Our 3-D thermoregulatory virtual human model consistently predicted the body's thermal state accurately for each of the simulated hot and cold environmental conditions and exertional heat stress. As such, it serves as a reliable tool to assess whole body, localized tissue, and, potentially, organ-specific injury risks, helping develop injury prevention and mitigation strategies in a systematic and expeditious manner. NEW & NOTEWORTHY This work provides a new, unified modeling framework to accurately predict the human body's thermal response to both heat and cold stress caused by environmental conditions and exertional physical activity in one mathematical model. We show that this 3-D anatomically detailed model accurately predicts the spatiotemporal temperature distribution in the body under extreme conditions for exposures to air and water and could be used to help design medical interventions and countermeasures to prevent injuries.