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Flexibility as a marker of early cognitive decline in humanized apolipoprotein ε 84 (ApoE4) mice

NEUROBIOLOGY OF AGING 2021年 102卷 129-138页

作者： Schmitt, Julien Paradis, Anne-Lise Boucher, Mathieu Andrieu, Laurent Barneoud, Pascal Rondi-Reig, Laure Sorbonne Univ Inst Biol Paris Seine IBPS Cerebellum Nav & Memory Team CeZaMe INSERMNeurosci Paris Seine NPSCNRS Paris France Sanofi R&D Rare & Neurol Dis Res Neurodegenerat Cluster Chilly Mazarin France IT&M STATS Neuilly Sur Seine France Sanofi R&D Biostat & Programming Dept Nonclin Efficacy & Safety Team Paris France

To test the hypothesis that ApoE4 may be involved in cognitive deficits associated with aging, we investigated the impact of APOE4 status and aging on the flexibility and memory components of spatial learning in mice. Young adult (6 months) and middle-aged (14 months) ApoE4, ApoE3 and C57BL/6 male mice were tested for flexibility in an aquatic Y-maze, and for spatio-temporal memory acquisition in the Starmaze. Our results revealed a flexibility deficit of the 6-month-old ApoE4 mice compared to controls. However, this deficit was not associated with spatio-temporal memory deficit at the same age. Importantly, the ApoE4 flexibility deficit did not increase with age, nor turn into memory deficit, or was able to predict individual variations of memory performance at 14 months. By contrast, control ApoE3 mice showed a decline of flexibility at 14 months resulting in performance similar to that of ApoE4. Overall, our results suggest that ApoE4 could be associated with an acceleration of the flexibility decrease otherwise observed in normal aging. (c) 2021 Elsevier Inc. All rights reserved.

关键词： ApoE4 Flexibility Reversal Learning Spatio-temporal memory Aging Navigation behavior

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Improved patient-reported outcomes with iGlarLixi versus premix BIAsp 30 in people with type 2 diabetes in the SoliMix trial

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DIABETES OBESITY & METABOLISM 2022年第12期24卷 2364-2372页

作者： Polonsky, William H. Giorgino, Francesco Rosenstock, Julio Whitmire, Katherine Lew, Elisheva Coudert, Mathieu Alvarez, Agustina Nicholls, Charlie McCrimmon, Rory J. Behav Diabet Inst 5230 Carroll Canyon Rd San Diego CA 92121 USA Univ Bari Aldo Moro Dept Emergency & Organ Transplantat Sect Internal Med Endocrinol Androl & Metab Dis Bari Italy Dallas Diabet Res Ctr Med City Dallas TX USA Southwest Med Associates Las Vegas NV USA Sanofi Chilly Mazarin France Sanofi Biostat & Programming Dept Chilly Mazarin France Sanofi Buenos Aires DF Argentina Sanofi Reading Berks England Univ Dundee Sch Med Div Syst Med Dundee Scotland

Aim To assess patient-reported outcomes (PROs) in the SoliMix trial, which compared the efficacy and safety of iGlarLixi versus BIAsp 30 in people with type 2 diabetes (T2D). Materials and Methods SoliMix (EudraCT: 2017-003370-13), a 26-week, open-label study, randomized (1:1) 887 adults with T2D and HbA1c >= 7.5%-<= 10.0% (>= 58-<= 86 mmol/mol) on basal insulin plus oral antihyperglycaemic drugs (OADs) to once-daily iGlarLixi or twice-daily premix insulin, BIAsp 30. PROs were assessed using the Treatment-Related Impact Measure Diabetes (TRIM-D) and Global Treatment Effectiveness Evaluation (GTEE) questionnaires. Results Over 26 weeks, iGlarLixi showed greater improvement from baseline versus BIAsp 30 in total TRIM-D score (least squares mean difference [95% confidence interval]: 5.08 [3.69, 6.47];effect size: 0.32) and in each TRIM-D domain, with the greatest differences seen in diabetes management (8.47 [6.11, 10.84]) and treatment burden (6.95 [4.83, 9.07]). GTEE scores showed a greater proportion of participants and physicians rated a complete or marked improvement of diabetes control with iGlarLixi (80.5%, 82.8%) versus BIAsp 30 (63.3%, 65.1%) at week 26. Post hoc analyses showed that after adjusting for HbA1c, body weight and hypoglycaemia outcomes, iGlarLixi continued to show greater improvements in TRIM-D total scores versus BIAsp 30. Conclusions In addition to better glycaemic control, weight benefit and less hypoglycaemia, once-daily iGlarLixi provided improved diabetes management, treatment burden and perceived effectiveness versus twice-daily premix BIAsp 30, further supporting iGlarLixi as an advanced treatment option in people with suboptimally controlled T2D on basal insulin plus OADs.

关键词： basal insulin GLP-1 analogue glycaemic control iGlarLixi patient-reported outcomes type 2 diabetes

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Child Abuse Pediatricians Assess a Low Likelihood of Abuse in Half of 2890 Physical Abuse Consults

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CHILD MALTREATMENT 2022年第2期27卷 202-208页

作者： Johnson, Katie L. Brown, Emily C. B. Feldman, Kenneth W. Qu, Pingping Lindberg, Daniel M. Seattle Childrens Hosp Dept Pediat Safe Child & Adolescent Network SCAN Seattle WA 98105 USA Univ Washington Sch Med Seattle WA USA Seattle Childrens Res Inst Biostat Epidemiol Econometr & Programming BEEP Co Seattle WA USA Univ Colorado Dept Emergency Med Anschutz Med Campus Aurora CO USA Univ Colorado Kempe Ctr Prevent & Treatment Child Abuse & Negle Anschutz Med Campus Aurora CO USA

The aim of this study was to examine the frequency with which child abuse pediatricians (CAPs) assess consultations as low versus high likelihood of abuse. In this retrospective secondary analysis of data from the Examining Siblings to Recognize Abuse (ExSTRA) study, the likelihood of abuse score for 2890 consultations at 20 medical centers was collected. Descriptive statistics were used to examine the percentage of cases representing low versus high likelihood of abuse (i.e., score of 1-4 vs. 5-7 on a 7-point scale). Linear and logistic regression analyses were used to examine score variability between medical centers. Overall, fifty-three percent of cases were assessed as low likelihood of abuse, suggesting that CAPs were equally as likely to assess a high versus low likelihood of abuse. The percentage of cases representing low likelihood of abuse differed significantly (P < .001) between medical centers after controlling for patient age, sex, race/ethnicity, twin/triplet status, injury types, and injury severity. The variability between CAP assessments at different medical centers is discussed, along with potential contributors to this variability and directions for future work.

关键词： child abuse physical abuse assessment decision making systems

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Participant Engagement and Symptom Improvement: Aripiprazole Tablets with Sensor for the Treatment of Schizophrenia

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PATIENT PREFERENCE AND ADHERENCE 2022年 16卷 1805-1817页

作者： Cochran, Jeffrey M. Fang, Hui Le Gallo, Christophe Peters-Strickland, Timothy Lindenmayer, Jean-Pierre Reuteman-Fowler, Corey Otsuka Pharmaceut Dev & Commercializat Inc Med & Real World Data Analyt Princeton NJ USA Otsuka Pharmaceut Dev & Commercializat Inc Biostat Princeton NJ USA Otsuka Pharmaceut Dev & Commercializat Inc Clin Programming Princeton NJ USA PPD Inc Wilmington NC USA New York Univ Grossman Sch Med Dept Psychiat New York NY USA Otsuka Pharmaceut Dev & Commercializat Inc Global Clin Dev Princeton NJ USA Otsuka Pharmaceut Dev & Commercializat Inc Med & Real World Data Analyt 508 Carnegie Ctr Princeton NJ 08540 USA

Purpose: A recent, phase 3b, mirror-image clinical trial of outpatients with schizophrenia found that use of aripiprazole tablets with sensor (AS;Abilify MyCite (R), comprising an ingestible event-marker sensor embedded in aripiprazole tablets, wearable sensor patches, and a smartphone application) reduced the incidence of psychiatric hospitalizations relative to oral standard-of-care antipsychotics. This analysis explored the relationship between AS engagement by participants and changes in participant performance and symptom-severity measures assessed by clinical raters. Participants and Methods: This post hoc analysis used prospectively collected clinical data from a phase 3b clinical trial (NCT03892889). Outpatients had schizophrenia, were aged 18-65 years, and had & GE;1 psychiatric hospitalization in the previous 48 months. Participants were grouped by study completion status and a k-means clustering algorithm based on AS utilization, resulting in 3 groups: discontinued (discontinued AS before month 3 of the study);moderate engagement (completed 3 months, used AS intermittently);and high engagement (completed 3 months, used AS regularly). Baseline to end-of-study differences for the Clinical Global Impression Scale (Severity of Illness and Improvement of Illness scales), Personal and Social Performance Scale, and Positive and Negative Syndrome Scale were calculated. Results: A total of 277 outpatients were enrolled (discontinued, n = 164;moderate engagement, n = 63;high engagement, n = 50). All groups experienced symptom improvement from baseline to end-of-study, with significant changes in the more-engaged groups. Highly engaged participants showed significant improvement for all clinical scores and subscores (all P < 0.05) and demonstrated significantly more improvement in symptoms than participants with less engagement. Conclusion: Participants who completed 3 months of the study and had higher AS engagement experienced significantly greater improvement in

关键词： digital medicine medication ingestion treatment utilization Positive and Negative Syndrome Scale

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Design and monitoring of survival trials based on restricted mean survival times

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CLINICAL TRIALS 2019年第6期16卷 616-625页

作者： Luo, Xiaodong Huang, Bo Quan, Hui Sanofi US Dept Biostat & Programming Res & Dev Bridgewater NJ 08807 USA Pfizer Inc New London CT USA

Background/Aims: Restricted mean survival time has become a popular treatment effect measurement because of its nice interpretability. However, study design based on restricted mean survival times often requires extensive simulation studies as the variance structure is hard to obtain analytically. This article aims to provide a flexible approach to conduct study design and monitoring based on the restricted mean survival times without resorting to simulation. Methods: We assume that both the event time and censoring time distributions are piecewise exponential, and the accrual distribution is piecewise uniform, with which the restricted mean survival times and their variance-covariance structure can be conveniently computed. Results: Since we allow arbitrary number of pieces in the piecewise exponential and uniform distributions, the resulting model can handle a wide range of scenarios. The usefulness of the approach is demonstrated via an example. Conclusion: The proposed approach is flexible and useful in the design and monitoring of survival trials based on restricted mean survival times.

关键词： Restricted mean survival times survival trials design and monitoring piecewise exponential non-uniform accrual

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Bias reduction using surrogate endpoints as auxiliary variables

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ANNALS OF THE INSTITUTE OF STATISTICAL MATHEMATICS 2019年第4期71卷 837-852页

作者： Takagi, Yoshiharu Kano, Yutaka Sanofi KK Biostat & Programming Tokyo 1631488 Japan Osaka Univ Div Math Sci Grad Sch Engn Sci Toyonaka Osaka 5608531 Japan

Recently, it is becoming more active to apply appropriate statistical methods dealing with missing data in clinical trials. Under not missing at random missingness, MLE based on direct-likelihood, or observed likelihood, possibly has a serious bias. A solution to the bias problem is to add auxiliary variables such as surrogate endpoints to the model for the purpose of reducing the bias. We theoretically studied the impact of an auxiliary variable on MLE and evaluated the bias reduction or inflation in the case of several typical correlation structures.

关键词： Auxiliary variables Surrogate endpoints Direct-likelihood Not missing at random missingness data

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Pharmacokinetics, Pharmacodynamics, Efficacy and Safety of a Romiplostim Biosimilar in Chronic Refractory Immune Thrombocytopenic Purpura (ITP) Patients

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INDIAN JOURNAL OF HEMATOLOGY AND BLOOD TRANSFUSION 2022年第1期38卷 111-121页

作者： Singh, Inderjeet Swetha, R. K. Patel, Ronak Dahiya, Meghana Jose, Vinu Intas Pharmaceut Ltd Biopharma Clin Dev & Med Affairs Ahmadabad Gujarat India Lambda Therapeut Res Ltd Biostat & Programming Ahmadabad Gujarat India Unique Hosp Multispecial & Res Inst Surat Gujarat India Paras HMRI Hosp Patna Bihar India HCG Hosp Ahmadabad Gujarat India Artemis Hosp Gurgaon Haryana India St Johns Med Coll & Hosp Bangalore Karnataka India Sahyadri Hosp Ltd Pune Maharashtra India Inst Haematol & Transfus Med Kolkata W Bengal India Christian Med Coll & Hosp Vellore Tamil Nadu India Apollo Hosp Chennai Tamil Nadu India

Romiplostim (Nplate (R), Amgen Inc.) is an orphan drug approved for the treatment of chronic refractory immune thrombolytic purpura (ITP) in adult and pediatric patients. Limited availability of pharmacokinetic (PK) data and large inter- and intra-subject variability in PK and platelet response is a challenge in the clinical development of a romiplostim biosimilar. We compared pharmacokinetics (PK), pharmacodynamics (PD)/efficacy, and safety of a romiplostim biosimilar with Nplate in 24 patients with ITP following a single 3 mu g/kg dose, and assessed efficacy of the romiplostim biosimilar at a titrated dose range of 1-5 mu g/kg in 50 patients with ITP. The PK of the romiplostim biosimilar did not differ compared to the PK of Nplate, and PD/efficacy responses were similar between the products following the single dose. The romiplostim biosimilar showed historically comparable PD/efficacy with Nplate over 8 weeks when treated at the titrated dose range. It was well tolerated in both the studies.

关键词： Romiplostim Biosimilar Immune thrombocytopenic Purpura Pharmacokinetics Pharmacodynamics Efficacy Safety

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Rejoinder to "on the alternative hypotheses for the win ratio"

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BIOMETRICS 2019年第1期75卷 352-354页

作者： Luo, Xiaodong Tian, Hong Mohanty, Surya Tsai, Wei Yann Sanofi US Dept Biostat & Programming Res & Dev Bridgewater NJ 08807 USA Janssen Res & Dev Raritan NJ 08869 USA Columbia Univ Dept Biostat New York NY 10032 USA

The article discusses about the potential use of the win ratio, focusing on the null hypothesis, expanding of the corresponding alternative hypothesis and the testing of null hypothesis against alternative hypothesis. It talks about the marginal hazards of hospitalization, the win probabilities, event time distribution, defining interpretable treatment that effect measures and eliminating the dependency on censoring distribution.

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Design and monitoring of survival trials in complex scenarios

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STATISTICS IN MEDICINE 2019年第2期38卷 192-209页

作者： Luo, Xiaodong Mao, Xuezhou Chen, Xun Qiu, Junshan Bai, Steven Quan, Hui Sanofi US Dept Biostat & Programming Res & Dev Bridgewater NJ 08807 USA FDA CDER Off Translat Sci Off BiostatDB1 Silver Spring MD USA

This paper proposes an approach to design and monitor survival trials accounting for complex scenarios such as delayed treatment effect, treatment dilution, and treatment crossover. These scenarios often lead to non-proportional hazards, making study design and monitoring more difficult. We demonstrate that, with event times following piecewise exponential distributions, the log-rank statistic as well as its variance-covariance structure can be easily computed, which greatly simplifies study design and monitoring. As the number of pieces in the exponential distributions can be arbitrary, this approach can handle a wide range of scenarios. Three hypothetical examples are used to demonstrate its potential use.

关键词： delayed treatment effect intent-to-treat non-uniform accrual piecewise exponential survival trials treatment crossover treatment dilution

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Implementing community-based health program in conflict settings: documenting experiences from the Central African Republic and South Sudan

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BMC HEALTH SERVICES RESEARCH 2023年第1期23卷 738-738页

作者： Rab, Faiza Razavi, Donya Kone, Mariam Sohani, Salim Assefa, Mekdes Tiwana, Muhammad Haaris Rossi, Rodolfo Univ Western Ontario Schulich Sch Med & Dent Dept Epidemiol & Biostat London ON Canada Canadian Red Cross Hlth Emergencies Ottawa ON Canada Canadian Red Cross Hlth Int Long Term Programming London ON Canada McMaster Univ Dept Hlth Aging & Soc Hamilton ON Canada Univ Western Ontario Masters Publ Hlth London ON Canada Int Comm Red Cross Hlth Unit Geneva Switzerland

BackgroundThe delivery of quality healthcare for women and children in conflict-affected settings remains a challenge that cannot be mitigated unless global health policymakers and implementers find an effective modality in these contexts. The International Committee of the Red Cross (ICRC) and the Canadian Red Cross (CRC) used an integrated public health approach to pilot a program for delivering community-based health services in the Central African Republic (CAR) and South Sudan in partnership with National Red Cross Societies in both countries. This study explored the feasibility, barriers, and strategies for context-specific agile programming in armed conflict affected *** qualitative study design with key informant interviews and focus group discussions using purposive sampling was used for this study. Focus groups with community health workers/volunteers, community elders, men, women, and adolescents in the community and key informant interviews with program implementers were conducted in CAR and South Sudan. Data were analyzed by two independent researchers using a content analysis *** total, 15 focus groups and 16 key informant interviews were conducted, and a total of 169 people participated in the study. The feasibility of service delivery in armed conflict settings depends on well-defined and clear messaging, community inclusiveness and a localized plan for delivery of services. Security and knowledge gaps, including language barriers and gaps in literacy negatively impacted service delivery. Empowering women and adolescents and providing context-specific resources can mitigate some barriers. Community engagement, collaboration and negotiating safe passage, comprehensive delivery of services and continued training were key strategies identified for agile programming in conflict *** an integrative community-based approach to health service delivery in CAR and South Sudan is feasible for humanitarian organi

关键词： Community based health services Reproductive Maternal Neonatal Child and Adolescent health services Armed conflict Protracted conflict Agile and responsive programing Community engagement The Central African Republic South Sudan RMNCAH

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