CDK12 phosphorylates 4E-BP1 to enable mTORC1-dependent translation and mitotic genome stability.

The RNA polymerase II (RNAPII) C-terminal domain kinase, CDK12, regulates genome stability, expression of DNA repair genes, and cancer cell resistance to chemotherapy and immunotherapy. In addition to its role in mRNA biosynthesis of DNA repair genes, we show here that CDK12 phosphorylates the mRNA 5' cap-binding repressor, 4E-BP1, to promote translation of mTORC1-dependent mRNAs. In particular, we found that phosphorylation of 4E-BP1 by mTORC1 (T37 and T46) facilitates subsequent CDK12 phosphorylation at two Ser-Pro sites (S65 and T70) that control the exchange of 4E-BP1 with eIF4G at the 5' cap of CHK1 and other target mRNAs. RNA immunoprecipitation coupled with deep sequencing (RIP-seq) revealed that CDK12 regulates release of 4E-BP1, and binding of eIF4G, to many mTORC1 target mRNAs, including those needed for MYC transformation. Genome-wide ribosome profiling (Ribo-seq) further identified specific CDK12 "translation-only" target mRNAs, including many mTORC1 target mRNAs as well as many subunits of mitotic and centromere/centrosome complexes. Accordingly, confocal imaging analyses revealed severe chromosome misalignment, bridging, and segregation defects in cells deprived of CDK12 or CCNK. We conclude that the nuclear RNAPII-CTD kinase CDK12 cooperates with mTORC1, and controls a specialized translation network that is essential for mitotic chromosome stability.

Epistemic misalignments in microbiome research.

We argue that microbiome research should be more reflective on the methods that it relies on to build its datasets due to the danger of facing a methodological problem which we call "epistemic misalignment." An epistemic misalignment occurs when the method used to answer specific scientific questions does not track justified answers, due to the material constraints imposed by the very method. For example, relying on 16S rRNA to answer questions about the function of the microbiome generates epistemic misalignments, due to the different temporal scales that 16S rRNA provides information about and the temporal scales that are required to know about the functionality of some microorganisms. We show how some of these exist in contemporary microbiome science and urge microbiome scientists to take some measures to avoid them, as they may question the credibility of the field as a whole.

Molecular-Level Dysregulation of Insulin Pathways and Inflammatory Processes in Peripheral Blood Mononuclear Cells by Circadian Misalignment.

Circadian misalignment due to night work has been associated with an elevated risk for chronic diseases. We investigated the effects of circadian misalignment using shotgun protein profiling of peripheral blood mononuclear cells taken from healthy humans during a constant routine protocol, which was conducted immediately after participants had been subjected to a 3-day simulated night shift schedule or a 3-day simulated day shift schedule. By comparing proteomic profiles between the simulated shift conditions, we identified proteins and pathways that are associated with the effects of circadian misalignment and observed that insulin regulation pathways and inflammation-related proteins displayed markedly different temporal patterns after simulated night shift. Further, by integrating the proteomic profiles with previously assessed metabolomic profiles in a network-based approach, we found key associations between circadian dysregulation of protein-level pathways and metabolites of interest in the context of chronic metabolic diseases. Endogenous circadian rhythms in circulating glucose and insulin differed between the simulated shift conditions. Overall, our results suggest that circadian misalignment is associated with a tug of war between central clock mechanisms controlling insulin secretion and peripheral clock mechanisms regulating insulin sensitivity, which may lead to adverse long-term outcomes such as diabetes and obesity. Our study provides a molecular-level mechanism linking circadian misalignment and adverse long-term health consequences of night work.

Internal circadian misallignment in a mouse model of chemotherapy induced fatigue.

BACKGROUND: Cancer survivors can experience long lasting fatigue resulting in a lower quality of life. How chemotherapy treatment contributes to this fatigue is poorly understood. Previously we have shown in a mouse model of cancer related fatigue that doxorubicin treatment induces fatigue-like symptoms related to disturbed circadian rhythms. However, the specific components of the circadian regulatory circuitry affected by doxorubicin treatment remained unclear. Therefore we investigated the role of the central circadian clock, the suprachiasmatic nucleus (SCN), in chemotherapy-induced fatigue. METHODS: We measured circadian controlled behavior and multiunit neuronal activity in the SCN in freely moving mice exhibiting fatigue-like behavior after doxorubicin treatment under both light-dark (LD) and constant dark (DD) conditions. Additionally, we assessed the expression of inflammation related genes in spleen and kidney as potential inducers of CRF. RESULTS: Doxorubicin treatment significantly reduced both the running wheel activity and time spent using the running wheel for over five weeks after treatment. In contrast to the pronounced effects on behavior and neuronal activity of doxorubicin on circadian rhythms, peripheral inflammation markers only showed minor differences, five weeks after the last treatment. Surprisingly, the circadian SCN neuronal activity under both LD and DD conditions was not affected. However, the circadian timing of neuronal activity in peri-SCN areas (the brain areas surrounding SCN) and circadian rest-activity behavior was strongly affected by doxorubicin, suggesting that the output of the SCN was altered. The reduced correlation between the SCN neuronal activity and behavioral activity after doxorubicin treatment, suggests that the information flow from the SCN to the periphery was disturbed. CONCLUSION: Our preclinical study suggests that chemotherapy-induced fatigue disrupts the circadian rhythms in peripheral brain areas and behavior downstream from the SCN, potentially leading to fatigue like symptoms. Our data suggest that peripheral inflammation responses are less important for the maintenance of fatigue. Chronotherapy that realigns circadian rhythms could represent a non-invasive way to improve patient outcomes following chemotherapy.

Leading edge of the a-wave of the electroretinogram and sodium iodate-induced age-related macular degeneration: A model.

BACKGROUND: Iron-induced oxidative stress was thought to be the reason why the a-wave amplitude of the electroretinogram (ERG) dropped when iron ions were present. It is assumed that reactive oxygen species (ROS) are generated in the presence of iron ions, and this leads to a decrease in hyperpolarization of the photoreceptor. It is known that in age-related macular degeneration (AMD), sodium iodate can induce oxidative stress, apoptosis, and retinal damage, which mimic the effects of clinical AMD. Here, the reduction of the a-wave amplitude in mice with sodium iodate-induced age-related macular degeneration is explained. METHODS: The leading edge of the a-wave is divided into voltages developed by cones and rods. The same oxidative stress model is applied here since sodium iodate causes the creation of ROS in a manner similar to that caused by iron ions, with the exception that the retina is treated as a circuit of various resistances when computing the photoresponse. Moreover, sodium iodate also leads to apoptosis and, hence, may cause misalignment in cones (not in rods) during the initial stage of apoptosis in AMD. To include the effects of apoptosis and shortening in cones and rods, we have used a factor representing the fraction of total cones and rods that are alive. To include the effect of misalignment of cones on the reduction of the a-wave amplitude, we have used the Stiles-Crawford function to calculate the number of photoisomerizations occurring in a photoreceptor misaligned at an angle θ. The results are compared with experimental data. RESULTS: In sodium iodate-treated eyes, the ROS produced can attract calcium ions in the photoreceptor, which increases the calcium influx. In the case of the cones, the inclusion of the misalignment angle in the phototransduction process helps in determining the voltage and slope of the voltage vs. time graph.The smaller the fraction of active photoreceptors, the smaller the amplitude of the a-wave. The calcium influx, misaligned photoreceptors, and total photoreceptor loss all cause the amplitude of the a-wave to decrease, and at any time from the beginning of phototransduction cascade, the calcium influx causes the slope of the a-wave to increase. CONCLUSION: The reduction in the a-wave amplitude in the eyes of sodium iodate-treated mice is attributed to oxidative stress in both cones and rods and cone misalignment, which ultimately lead to apoptosis and vision loss in AMD.

Associations of social jetlag with physical activity and sedentary behaviour in children and adolescents: A systematic review and meta-analysis.

Sleep and daytime movement behaviours occur co-dependently with each other within a finite 24 h day. Sleep parameters other than sleep duration, such as social jetlag and chronotype, have been linked to health problems and unhealthy behaviours among children and adolescents. Given the increasing number of studies examining sleep timing/chronotype and weight-related behaviours, including physical activity and sedentary behaviour, in the past decade, this systematic review and meta-analysis collated and evaluated the evidence on the relationships of social jetlag and chronotype with physical activity and sedentary behaviour among children and adolescents aged 3-17 years. Seven databases were searched on 16 March 2022, and 52 studies were identified as eligible for inclusion, 47 of which were suitable for the meta-analysis. A positive association was found between social jetlag and screen media use (r = 0.14, 95% CI: 0.04-0.24; I2 = 96%; p = 0.008). The morning chronotype was associated with a higher level of physical activity and a lower level of sedentary behaviour than the evening chronotype. No relationship was found between social jetlag and physical activity. The magnitude of heterogeneity among the included studies was high. Further experimental studies are urgently required to understand how circadian preference or misalignment affects activity behaviours. Interventions to promote an active lifestyle in young populations should consider their circadian preference, especially among individuals with the evening chronotype.

Circadian misalignment impairs oligodendrocyte myelination via Bmal1 overexpression leading to anxiety and depression-like behaviors.

Circadian misalignment (CM) caused by shift work can increase the risk of mood impairment. However, the pathological mechanisms underlying these deficits remain unclear. In the present study, we used long-term variable photoperiod (L-VP) in wild-type mice to better simulate real-life shift patterns and study its effects on the prefrontal cortex (PFC) and hippocampus, which are closely related to mood function. The results showed that exposure to L-VP altered the activity/rest rhythms of mice, by eliciting phase delay and decreased amplitude of the rhythms. Mice with CM developed anxiety and depression-like manifestations and the number of mature oligodendrocytes (OL) was reduced in the medial prefrontal cortex and hippocampal CA1 regions. Mood impairment and OL reduction worsened with increased exposure time to L-VP, while normal photoperiod restoration had no effect. Mechanistically, we identified upregulation of Bmal1 in the PFC and hippocampal regions of CM mice at night, when genes related to mature OL and myelination should be highly expressed. CM mice exhibited significant inhibition of the protein kinase B (AKT)/mTOR signaling pathway, which is directly associated to OL differentiation and maturation. Furthermore, we demonstrated in the OL precursor cell line Oli-Neu that overexpression of Bmal1 inhibits AKT/mTOR pathway and reduces the expression of genes OL differentiation. In conclusion, BMAL1 might play a critical role in CM, providing strong research evidence for BMAL1 as a potential target for CM therapy.

Glycemic response to meals with a high glycemic index differs between morning and evening: a randomized cross-over controlled trial among students with early or late chronotype.

PURPOSE: Glycemic response to the same meal depends on daytime and alignment of consumption with the inner clock, which has not been examined by individual chronotype yet. This study examined whether the 2-h postprandial and 24-h glycemic response to a meal with high glycemic index (GI) differ when consumed early or late in the day among students with early or late chronotype. METHODS: From a screening of 327 students aged 18-25 years, those with early (n = 22) or late (n = 23) chronotype participated in a 7-day randomized controlled cross-over intervention study. After a 3-day observational phase, standardized meals were provided on run-in/washout (days 4 and 6) and intervention (days 5 and 7), on which participants received a high GI meal (GI = 72) in the morning (7 a.m.) or in the evening (8 p.m.). All other meals had a medium GI. Continuous glucose monitoring was used to measure 2-h postprandial and 24-h glycemic responses and their variability. RESULTS: Among students with early chronotype 2-h postprandial glucose responses to the high GI meal were higher in the evening than in the morning (iAUC: 234 (± 92) vs. 195 (± 91) (mmol/L) × min, p = 0.042). Likewise, mean and lowest 2-h postprandial glucose values were higher when the high GI meal was consumed in the evening (p < 0.001; p = 0.017). 24-h glycemic responses were similar irrespective of meal time. Participants with late chronotype consuming a high GI meal in the morning or evening showed similar 2-h postprandial (iAUC: 211 (± 110) vs. 207 (± 95) (mmol/L) × min, p = 0.9) and 24-h glycemic responses at both daytimes. CONCLUSIONS: Diurnal differences in response to a high GI meal are confined to those young adults with early chronotype, whilst those with a late chronotype seem vulnerable to both very early and late high GI meals. Registered at clinicaltrials.gov (NCT04298645; 22/01/2020).

Controls, comparator arms, and designs for critical care comparative effectiveness research: It's complicated.

BACKGROUND: Comparative effectiveness research is meant to determine which commonly employed medical interventions are most beneficial, least harmful, and/or most costly in a real-world setting. While the objectives for comparative effectiveness research are clear, the field has failed to develop either a uniform definition of comparative effectiveness research or an appropriate set of recommendations to provide standards for the design of critical care comparative effectiveness research trials, spurring controversy in recent years. The insertion of non-representative control and/or comparator arm subjects into critical care comparative effectiveness research trials can threaten trial subjects' safety. Nonetheless, the broader scientific community does not always appreciate the importance of defining and maintaining critical care practices during a trial, especially when vulnerable, critically ill populations are studied. Consequently, critical care comparative effectiveness research trials sometimes lack properly constructed control or active comparator arms altogether and/or suffer from the inclusion of "unusual critical care" that may adversely affect groups enrolled in one or more arms. This oversight has led to critical care comparative effectiveness research trial designs that impair informed consent, confound interpretation of trial results, and increase the risk of harm for trial participants. METHODS/EXAMPLES: We propose a novel approach to performing critical care comparative effectiveness research trials that mandates the documentation of critical care practices prior to trial initiation. We also classify the most common types of critical care comparative effectiveness research trials, as well as the most frequent errors in trial design. We present examples of these design flaws drawn from past and recently published trials as well as examples of trials that avoided those errors. Finally, we summarize strategies employed successfully in well-designed trials, in hopes of suggesting a comprehensive standard for the field. CONCLUSION: Flawed critical care comparative effectiveness research trial designs can lead to unsound trial conclusions, compromise informed consent, and increase risks to research subjects, undermining the major goal of comparative effectiveness research: to inform current practice. Well-constructed control and comparator arms comprise indispensable elements of critical care comparative effectiveness research trials, key to improving the trials' safety and to generating trial results likely to improve patient outcomes in clinical practice.

Development, validation, and reliability of the Chrononutrition Profile Questionnaire-Pregnancy (CPQ-P).

BACKGROUND: During pregnancy, physiological changes can affect eating and sleeping habits, which may eventually have negative consequences for maternal and foetal health. To better understand these changes, it is essential to develop a reliable questionnaire that addresses lifestyle habits such as snacking and daytime napping. This study aimed to determine the validity and reliability of the Chrononutrition Profile Questionnaire-Pregnancy (CPQ-P). METHODS: A total of 399 women in their second and third trimester of pregnancy were recruited from government maternal and child health clinics in Kuala Lumpur and Putrajaya and completed a self-administered online questionnaire. Content validity was conducted with an expert panel consisting of 4 members. Confirmatory factor analysis (CFA) using maximum likelihood was conducted to determine the construct validity. Internal consistency was determined by Cronbach's alpha coefficient (CAC), while the test-retest reliability was conducted using intraclass correlation coefficient (ICC). RESULTS: The questionnaire had an appropriate content validity index of 0.91. The CPQ-P consists of 22 items, measuring 5 constructs, including morning chrono-habits, sleeping habits, evening eating, temporal eating, and pregnancy symptoms. The factor model showed good fit with χ2/df = 2.486, GFI = 0.893, CFI = 0.912, and RMSEA = 0.065. The 22 items in CPQ-P showed fair to excellent test-retest reliability (ICC: 0.42 to 0.98). The 5 constructs in CPQ-P were found to have a good to excellent internal consistency (α = 0.612-0.963). CONCLUSIONS: The CPQ-P is a valid and reliable tool for assessing lifestyle habits during pregnancy. The questionnaire can be used to identify areas where pregnant women may need additional support or intervention to adopt healthy behaviours and reduce the risk of adverse maternal and foetal outcomes. TRIAL REGISTRATION: NCT05700136 (clinicaltrials.gov). Trial registration date: 26/01/2023.

Association between glucose dips and the feeling of hunger in a dietary intervention study among students with early and late chronotype-secondary analysis of a randomized cross-over nutrition trial.

Consumption of foods with high glycaemic index (GI) can cause hyperglycemia, thus increasing postprandial hunger. Since circadian rhythm differs inter-individually, we describe glucose dips after breakfast/dinner with high/medium estimated meal GI among students with early (n = 22) and late chronotype (n = 23) and examine their relation to the feeling of hunger in a secondary analysis of a randomized cross-over nutrition trial. Glucose dips reflect the difference between the lowest glucose value recorded 2-3 h postprandially and baseline, presented as percentage of average baseline level. Associations between glucose dips and the feeling of hunger were analyzed using multilevel linear models. Glucose dips were lower after medium GI meals than after high GI meals among both chronotype groups (p = 0.03). Among early chronotypes, but not among late chronotypes, glucose dip values were lower after breakfast than after dinner (-4.9 % vs. 5.5 %, p = 0.001). Hunger increased throughout the day among both chronotypes but glucose dips were not related to the feeling of hunger at the meal following breakfast. Interestingly, lower glucose dip values 2-3 h postprandially occurred particularly after medium GI meals and were seen after breakfast among early chronotypes. These glucose dips did not predict hunger at meals after breakfast.

Impact of operative position on rotational alignment after intramedullary nailing of trochanteric fractures: a comparative analysis of lateral decubitus versus supine position.

BACKGROUND: Fixation of trochanteric fractures with an intramedullary nail in a non-physiological position can cause poor functional outcomes. The aim of this study is to evaluate the effect of intraoperative patient position on rotational alignment in intramedullary nail fixation of trochanteric fractures. METHODS: The femoral rotational alignment of 84 trochanteric fracture patients who underwent intramedullary nailing was measured by computed tomography (CT) images. Patients were divided into two groups: the supine position on the fracture table (FT) (Group 1, n = 42) and the lateral decubitus (LD) position (Group 2, n = 42). Femoral malrotation angles were measured and divided into three subgroups: insignificant, significant, and excessive. The number of intraoperative fluoroscopy images, preparation time, surgery time, and anesthesia time in both groups were compared. RESULTS: The malrotation degrees of patients in Group 1 ranged from 17° external rotation (ER) to 57° internal rotation (IR), with a mean of 10° IR. Of the patients in Group 1, 27 were insignificant, 5 were significant, and 10 were in the excessive subgroup. The malrotation degrees of patients in Group 2 ranged from 33° ER to 47° IR, with a mean of 11° IR. Of the patients in Group 2, 21 were insignificant, 12 were significant, and 9 were in the excessive subgroup. There was no statistically significant relationship between patient position and malrotation angle. The number of intraoperative fluoroscopy images, preparation time, and anesthesia time were statistically lower in Group 2. There was no statistically significant difference between Group 1 and Group 2 in terms of surgery time. CONCLUSION: Intramedullary nailing in the LD position is a reliable and practical surgical method in the treatment of femoral trochanteric fractures since there is no need for the use of a FT, the surgeon is exposed to less radiation, there is no risk of complications related to the traction of the FT, and there is a shorter operation time.

The endogenous circadian system worsens asthma at night independent of sleep and other daily behavioral or environmental cycles.

Asthma often worsens at night. To determine if the endogenous circadian system contributes to the nocturnal worsening of asthma, independent of sleep and other behavioral and environmental day/night cycles, we studied patients with asthma (without steroid use) over 3 wk in an ambulatory setting (with combined circadian, environmental, and behavioral effects) and across the circadian cycle in two complementary laboratory protocols performed in dim light, which separated circadian from environmental and behavioral effects: 1) a 38-h "constant routine," with continuous wakefulness, constant posture, 2-hourly isocaloric snacks, and 2) a 196-h "forced desynchrony" incorporating seven identical recurring 28-h sleep/wake cycles with all behaviors evenly scheduled across the circadian cycle. Indices of pulmonary function varied across the day in the ambulatory setting, and both laboratory protocols revealed significant circadian rhythms, with lowest function during the biological night, around 4:00 AM, uncovering a nocturnal exacerbation of asthma usually unnoticed or hidden by the presence of sleep. We also discovered a circadian rhythm in symptom-based rescue bronchodilator use (ß2-adrenergic agonist inhaler) whereby inhaler use was four times more likely during the circadian night than day. There were additive influences on asthma from the circadian system plus sleep and other behavioral or environmental effects. Individuals with the lowest average pulmonary function tended to have the largest daily circadian variations and the largest behavioral cycle effects on asthma. When sleep was modeled to occur at night, the summed circadian, behavioral/environmental cycle effects almost perfectly matched the ambulatory data. Thus, the circadian system contributes to the common nocturnal worsening of asthma, implying that internal biological time should be considered for optimal therapy.

Varus-valgus alignment of humeral short stem in reverse total shoulder arthroplasty: does it really matter?

BACKGROUND: The utilization of short humeral stems in reverse total shoulder arthroplasty has gained attention in recent times. However, concerns regarding the risk of misalignment during implant insertion are associated with their use. METHODS: Eight fresh-frozen cadaveric shoulders were prepared for dissection and biomechanical testing. A bespoke humeral implant was fabricated to facilitate assessment of neutral, varus, and valgus alignments using a single stem, and 10° was established as the maximum permissible angle for misalignments. Shift in humerus position and changes in deltoid length attributable to misalignments relative to the neutral position were evaluated using a Microscribe 3DLx system. The impingement-free range of motion, encompassing abduction, adduction, internal rotation, and external rotation (ER), was gauged using a digital goniometer. The capacity for abduction was evaluated at maximal abduction angles under successive loading on the middle deltoid. A specialized traction system coupled with a force transducer was employed to measure anterior dislocation forces. RESULTS: Relative to the neutral alignment, valgus alignment resulted in a more distal (10.5 ± 2.4 mm) and medial (8.3 ± 2.2 mm) translation of the humeral component, whereas the varus alignment resulted in the humerus shifting more superiorly (11.2 ± 1.3 mm) and laterally (9.9 ± 0.9 mm) at 0° abduction. The valgus alignment exhibited the highest abduction angle than neutral alignment (86.2°, P < .001). Conversely, the varus alignment demonstrated significantly higher adduction (18.4 ± 7.4°, P < .001), internal rotation (68.9 ± 15.0°, P = .014), and ER (45.2 ± 10.5°, P = .002) at 0° abduction compared to the neutral alignments. Anterior dislocation forces were considerably lower (23.8 N) in the varus group compared to the neutral group at 0°ER (P = .047). Additionally, abduction capability was markedly higher in varus alignment at low deltoid loads than the neutral alignment (5N, P = .009; 7.5 N, P = .007). CONCLUSIONS: The varus position enhances rotational range of motion (ROM) but increases instability, while the valgus position does not significantly impact ROM or instability compared to the neutral position.

Sensor Fusion for Underwater Vehicle Navigation Compensating Misalignment Using Lie Theory.

This paper presents a sensor fusion method for navigation of unmanned underwater vehicles. The method combines Lie theory into Kalman filter to estimate and compensate for the misalignment between the sensors: inertial navigation system and Doppler Velocity Log (DVL). In the process and measurement model equations, a 3-dimensional Euclidean group (SE(3)) and 3-sphere space (S3) are used to express the pose (position and attitude) and misalignment, respectively. SE(3) contains position and attitude transformation matrices, and S3 comprises unit quaternions. The increments in pose and misalignment are represented in the Lie algebra, which is a linear space. The use of Lie algebra facilitates the application of an extended Kalman filter (EKF). The previous EKF approach without Lie theory is based on the assumption that a non-differentiable space can be approximated as a differentiable space when the increments are sufficiently small. On the contrary, the proposed Lie theory approach enables exact differentiation in a differentiable space, thus enhances the accuracy of the navigation. Furthermore, the convergence and stability of the internal parameters, such as the Kalman gain and measurement innovation, are improved.

Errors in Estimating Lower-Limb Joint Angles and Moments during Walking Based on Pelvic Accelerations: Influence of Virtual Inertial Measurement Unit's Frontal Plane Misalignment.

The accurate estimation of lower-limb joint angles and moments is crucial for assessing the progression of orthopedic diseases, with continuous monitoring during daily walking being essential. An inertial measurement unit (IMU) attached to the lower back has been used for this purpose, but the effect of IMU misalignment in the frontal plane on estimation accuracy remains unclear. This study investigated the impact of virtual IMU misalignment in the frontal plane on estimation errors of lower-limb joint angles and moments during walking. Motion capture data were recorded from 278 healthy adults walking at a comfortable speed. An estimation model was developed using principal component analysis and linear regression, with pelvic accelerations as independent variables and lower-limb joint angles and moments as dependent variables. Virtual IMU misalignments of -20°, -10°, 0°, 10°, and 20° in the frontal plane (five conditions) were simulated. The joint angles and moments were estimated and compared across these conditions. The results indicated that increasing virtual IMU misalignment in the frontal plane led to greater errors in the estimation of pelvis and hip angles, particularly in the frontal plane. For misalignments of ±20°, the errors in pelvis and hip angles were significantly amplified compared to well-aligned conditions. These findings underscore the importance of accounting for IMU misalignment when estimating these variables.

Overview of Radar Alignment Methods and Analysis of Radar Misalignment's Impact on Active Safety and Autonomous Systems.

The rapid development of active safety systems in the automotive industry and research in autonomous driving requires reliable, high-precision sensors that provide rich information about the surrounding environment and the behaviour of other road users. In practice, there is always some non-zero mounting misalignment, i.e., angular inaccuracy in a sensor's mounting on a vehicle. It is essential to accurately estimate and compensate for this misalignment further programmatically (in software). In the case of radars, imprecise mounting may result in incorrect/inaccurate target information, problems with the tracking algorithm, or a decrease in the power reflected from the target. Sensor misalignment should be mitigated in two ways: through the correction of an inaccurate alignment angle via the estimated value of the misalignment angle or alerting other components of the system of potential sensor degradation if the misalignment is beyond the operational range. This work analyses misalignment's influences on radar sensors and other system components. In the mathematically proven example of a vertically misaligned radar, pedestrian detectability dropped to one-third of the maximum range. In addition, mathematically derived heading estimation errors demonstrate the impact on data association in data fusion. The simulation results presented show that the angle of misalignment exponentially increases the risk of false track splitting. Additionally, the paper presents a comprehensive review of radar alignment techniques, mostly found in the patent literature, and implements a baseline algorithm, along with suggested key performance indicators (KPIs) to facilitate comparisons for other researchers.

An Improved Initial Alignment Method Based on SE2(3)/EKF for SINS/GNSS Integrated Navigation System with Large Misalignment Angles.

This paper proposes an improved initial alignment method for a strap-down inertial navigation system/global navigation satellite system (SINS/GNSS) integrated navigation system with large misalignment angles. Its methodology is based on the three-dimensional special Euclidean group and extended Kalman filter (SE2(3)/EKF) and aims to overcome the challenges of achieving fast alignment under large misalignment angles using traditional methods. To accurately characterize the state errors of attitude, velocity, and position, these elements are constructed as elements of a Lie group. The nonlinear error on the Lie group can then be well quantified. Additionally, a group vector mixed error model is developed, taking into account the zero bias errors of gyroscopes and accelerometers. Using this new error definition, a GNSS-assisted SINS dynamic initial alignment algorithm is derived, which is based on the invariance of velocity and position measurements. Simulation experiments demonstrate that the alignment method based on SE2(3)/EKF can achieve a higher accuracy in various scenarios with large misalignment angles, while the attitude error can be rapidly reduced to a lower level.

Sleep-wake behavior, perceived fatigability, and cognitive reserve in older adults.

INTRODUCTION: The effects of sleep-wake behavior on perceived fatigability and cognitive abilities when performing daily activities have not been investigated across levels of cognitive reserve (CR). METHODS: CR Index Questionnaire (CRIq) data were collected and subjected to moderated mediation analysis. RESULTS: In amnestic mild cognitive impairment (aMCI; n = 41), CR moderated sleep-related impairments (SRIs), and fatigability at low CR (CRIq < 105.8, p = 0.004) and mean CR (CRIq = 126.9, p = 0.03) but not high CR (CRIq > 145.9, p = 0.65) levels. SRI affected cognitive abilities mediated by fatigability at low CR (p < 0.001) and mean CR (p = 0.003) levels. In healthy controls (n = 13), SRI in fatigability did not alter cognitive abilities across CR levels; controls had higher leisure scores than patients with aMCI (p = 0.003, effect size = 0.93). DISCUSSION: SRI can amplify impaired cognitive abilities through exacerbation of fatigability in patients with aMCI with below-mean CR. Therefore, improving sleep-wake regulation and leisure activities may protect against fatigability and cognitive decline. HIGHLIGHTS: Clinical fatigue and fatigability cannot be alleviated by rest. Clinical fatigability disrupts daily activities during preclinical Alzheimer's. High cognitive reserve mitigates sleep-wake disturbance effects. High cognitive reserve attenuates clinical fatigability effects on daily functioning. Untreated obstructive sleep apnea potentiates Alzheimer's pathology in the brain.

Maternal dietary and environmental factors associated with infant circadian rhythm, growth, and temperament: Research protocol for a prospective cohort study.

Introduction: Emerging evidence has been explored to determine the factors affecting the development of infant circadian rhythm. While fetal programming happens during the pregnancy period, external environmental cues and infant nutritional programming can have substantial effects on the infant circadian rhythm. Understanding prenatal and postnatal factors determining infant circadian rhythm can improve future interventions in optimizing maternal and infant health. Methods: This is a prospective observational cohort study, targeting 216 pregnant women from government maternity clinics in Kuala Lumpur, Malaysia. Pregnant women will be recruited at third trimester (baseline), and follow up at 3 months, and 6 months. A subsample will be collected for salivary cortisol analysis to determine circadian rhythm of the mother and infant at third trimester and 3 months. Data of eating misalignment, light exposure, chronotype, infant temperament, sleep quality, and mood will be collected via validated questionnaires. Anthropometric data and birth outcomes will be collected from antenatal and postnatal health records. Summary: Studies on infant circadian rhythm development have yet to be explored and established, hence this study presents a novel approach to identify the factors from prenatal to postnatal periods on infant circadian rhythm and its influence on growth and temperament. Findings from this study will provide insights in the critical timing which has larger effects on infant circadian rhythm development for future interventions to be conducted.