Background: Maternal gestational weight gain (GWG) may be associated with cardiovascular diseases in the offspring from childhood to adulthood. We aimed to investigate the association between maternal GWG and the left ventricle (LV) geometry and function in the offspring, and explore the influence of the intrauterine environment on early childhood cardiac change.Methods: Data of 981 mother-offspring pairs from the Shanghai Birth Cohort was used. Maternal pre-pregnancy weight and height, weight in the first trimester (≤ 12 weeks), and before delivery were measured. The echocardiography, blood pressure, and anthropometry assessment were evaluated in the offspring at 4 years of age.Results: Interventricular septal thickness during diastole had a significantly positive correlation with total GWG . In the second and third trimesters, LV mass index , interventricular septal thickness in systole , and in diastole  were positively associated with GWG. The risks of eccentric  and concentric hypertrophy  increased with the elevation of maternal GWG.Conclusions: This study suggested that the excessive maternal GWG was associated with the thickening of the interventricular septum in the offspring, especially during the second and third trimesters. Excessive GWG in the second and third trimesters was a risk factor for LV eccentric and concentric hypertrophy in the offspring. Left ventricle (LV) geometry and function are important factors that influence cardiac remodeling, and are also determinants of cardiovascular events in adulthood , 2. LV gThe LV geometry and functional changes are often evaluated in adults and adolescents. Morphologic changes in the LV could progress due to cumulative exposures from an early age, which could impair LV function ultimately in later life . HoweverApart from early influences during childhood, the LV geometry and function could also be affected by various maternal factors, such as obesity, gestational hypertension, and diabetes –9. GestaBased on the Shanghai Birth Cohort (SBC), we aimed to investigate the association of maternal GWG with offspring LV geometry and function at 4 years of age to explore the influence of the intrauterine environment on early childhood cardiac geometry and function.The SBC is an ongoing prospective cohort study conducted in six collaborating hospitals in Shanghai, China. Volunteer couples were recruited during preconception care or in early pregnancy from 2013 to 2016, and the mother-fetus pairs were followed from preconception or early pregnancy to the end of the gestation. A detailed description of the cohort has been provided elsewhere (2), normal weight (18.5–24.9 kg/m2), overweight (25.0–29.9 kg/m2), and obese (≥ 30.0 kg/m2) , reproductive characteristics , lifestyle factors , and history of gestational hypertension or diabetes were collected through structured questionnaires and extraction of the inpatient history of the pregnant women from medical records. Pre-pregnancy weight and height, weight in the first trimester (≤ 12 weeks), and weight before delivery were measured at each clinical visit. Maternal pre-pregnancy body mass index (BMI), total GWG, GWG in the first (≤ 12 weeks) or second and third trimesters (>12 weeks) were calculated. Based on the World Health Organization (WHO) criteria, the pre-pregnancy BMI was categorized as underweight (< 18.5 kg/m0 kg/m2) .The height and weight of the offspring were measured according to the standard protocol. BMI was calculated in the 4-year-old children. Blood pressure (BP) and heart rate (HR) of the 4-year-old children were assessed by one trained staff while they were supine using the OMRAN HBP-1300 automatic BP device  on the left arm at heart level and with the appropriate cuff size for arm circumference. Three measurements were taken at 5-min intervals. The mean of the measurements was used in all analyses.Transthoracic echocardiography examinations were performed for the children according to the American and European guidelines  by train2.7  was calculated by the sum of the thickness of the LV posterior wall in diastole (LVPWd) and interventricular septal thickness in diastole (IVSd), then divided by the internal LV diameter in diastole (LVDd) . LV mass2.7 .Pulse wave Doppler was used to measure the mitral early diastolic flow velocity (E), late diastolic flow velocity (A) to calculate the E/A ratio. The Doppler time intervals, including the ejection time (ET), isovolumic contraction time (ICT), and isovolumic relaxation time (IRT), were obtained at the mitral inflow and LV outflow tracts to calculate the Tei index, with the formula: Tei index = (ICT + IRT)/ET. These indices were used to assess the diastolic function of the LV.For 2D speckle-tracking analysis, 2D images of 3–5 cardiac cycles were collected and analyzed with the commercial Qlab version 10.5 software ] at a frame rate of ≥ 60/s. Peak longitudinal strain was measured in the apical four, two, and three-chamber and global peak longitudinal strain (GLS) was calculated using the strain value of each segment in LV.2.7, RWT = 0.27 in girls and LVMI = 33.76 g/m2.7, RWT = 0.27 in boys represented the sex-specific 95th percentiles in the cohort. Four groups were constructed for LV geometry patterns: (1) LVMI <33.24 g/m2.7 for girls and <33.76 g/m2.7 for boys, and RWT < 0.27 was classified as normal left ventricular geometry; (2) normal LVMI with increased RWT (>0.27) was classified as concentric remodeling; (3) increased LVMI , and normal RWT (<0.27) was defined as eccentric hypertrophy; and (4) increase in both variables was identified as concentric hypertrophy.The LV geometry patterns were defined using the LVMI and RWT according to Ganau and colleagues' descriptions . There wAll the examinations were performed by a single experienced operator. Both the sonographers and the observers were blinded to the participants' details.Linear regression models were used to investigate the associations between maternal GWG and offspring LV geometry and function changes. Five sets of models were constructed: the basic model was adjusted for none of the maternal factors or offspring factors. Model 1 was adjusted for maternal factors, including age at delivery, race, educational level, alcoholic drink intake history, exposure to passive smoke, pre-pregnancy BMI, gestational diabetes mellitus (GDM), and gestational hypertension or pre-eclampsia. Model 2 was adjusted additionally for gestational age, sex of offspring, delivery mode, and parity. Model 3 was adjusted additionally for BMI at 4 years of age. Model 4 was adjusted additionally for BP at 4 years of age. The GWG was divided into three groups according to the gestational trimesters as the total, first trimester, and second and third trimesters.To further eliminate the effect of pre-pregnancy BMI on the LV geometry and function change in offspring, the study population was stratified into three groups  according to the WHO criteria . Linear To test the risk of LV geometry pattern changes caused by an increase in GWG, including eccentric hypertrophy, concentric hypertrophy, and remodeling, multiple logistic regression analysis was performed in different groups, and odds ratio (OR) was calculated.Statistical analysis was carried out using the SPSS 19.0 software program . All tests were two-sided with a significance level of 0.05.The baseline characteristics of the study participants are presented in In the basic model , almost The gestational time was divided into the total, first trimester (≤ 12 weeks), and second and third trimesters (>12 weeks). In the basic model, LVMI , LVDd , IVSd , and IVSs  had a positive association with the second and third trimester GWG. GWG in the first trimester had no significant correlation with any structural and functional indices. After adjusting for maternal and offspring factors, LVMI , IVSs , and IVSd  continued to be positively associated with GWG in all models during the second and third trimesters. The RWT and the LV function indices had no significant correlation with GWG in any trimester.GWG was strongly related to pre-pregnancy BMI . Taking The risk of four types of LV geometry change patterns in offspring with maternal GWG in different trimesters is presented in In this prospective cohort study, we found that greater GWG was associated with LV morphologic changes in the offspring as early as 4 years of age, especially the thickening of IVS. Greater GWG during the second and third trimesters was an independent risk factor for LV eccentric and concentric hypertrophy in the offspring.Cardiac structural changes usually occur before global functional alteration, which is often evaluated during adulthood and adolescence. However, morphologic changes in the LV could progress due to accumulated exposures during childhood, which could impair the LV function ultimately in later life . In our LV wall thickening is the manifestation of myocardial hypertrophy . The thiWe focused on the LV geometry and functional patterns in a birth cohort comprising randomly selected children. These LV structural changes, including thickening of the IVS, may be physiologic during early childhood since the pathological changes usually occur in adolescents , 36 and Greater GWG was associated with many adverse maternal and offspring outcomes from birth to adulthood. Greater maternal pre-pregnancy weight and GWG were associated with higher systolic blood pressure , adverseThere are several possible explanations for the mechanisms responsible for a greater GWG increasing the risk of LVH. Greater maternal GWG is an abnormal metabolic state, which modifies the intrauterine environment, thereby influencing placental function and fetal programming of the cardiovascular system, which, in turn, affects fetal heart development. A mother with excessive weight gain or obesity has a suboptimal uterine nutritional climate, which may disrupt the inflammatory and hormone metabolic homeostasis of the mother, including insulin resistance, increased level of leptin, lipid, and pro-inflammatory cytokines. These metabolic disorders may change the placental hemodynamics causing placental vascular insufficiency, increased lipogenesis, infarction, hypoxia, and inflammatory activation . These mEarly screening of LV geometry and function by echocardiography at 4 years of age without the administration of any sedative agents was feasible. Thus, this age may be a suitable time for early screening. Furthermore, early screening of LV structural changes should be recommended in the offspring of mothers who had excessive weight gain during pregnancy, and emphasize the need for additional monitoring and weight management during the second and third trimesters.To our knowledge, this study was the largest prospective birth cohort study that assessed LV geometry and function using detailed echocardiography during early childhood in China. Furthermore, previous research on the association between maternal and offspring factors associated with LV geometry usually focused on maternal obesity  and wereOur study has several limitations. First, cardiac magnetic resonance imaging is the gold standard to evaluate LV geometry. However, this procedure requires the administration of sedatives in young children. Therefore, in our study, we opted for echocardiography as a more suitable modality for children aged 4 years. Second, data on maternal weight during the second trimester were not available in the medical records, which may need a more detailed investigation in future studies. Third, there was an unequal representation of the populations enrolled in our study regarding the different degrees of GWG and pre-pregnancy BMI, which may have influenced the results of the subgroup analysis.Excessive GWG, especially during the second and third trimesters, was associated with increased thickening of the IVS. Thus, excessive GWG during the second and third trimesters is a risk factor for LV eccentric and concentric hypertrophy at 4 years of age in the offspring. Our results provide evidence supporting the early screening of LV geometry and function during early childhood, and emphasize the need for additional monitoring and weight management of pregnant mothers during the second and third trimesters.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the research ethics boards of Shanghai Xinhua Hospital . Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.JW, BD, and YW drafted and revised the manuscript. JW, BD, YW, ZL, YW, SC, and KS contributed to the conception and design of the work. JW, BD, YW, ZL, and YY contributed to the acquisition of data. JW, BD, YW, QC, XZ, and ZL contributed to the analysis or interpretation of the data. YW, SC, and KS critically revised the manuscript. All authors gave their final approval and agreed to be accountable for all aspects of this work ensuring its integrity and accuracy.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


People living with cerebral palsy (CP) exhibit motor and sensory impairments that affect unimanual and bimanual functions. The importance of sensory functions for motor control is well known, but the association between motor and sensory functions remains unclear in people living with CP. The objective of this systematic review was to characterize the relationship between sensory deficits and upper limb motor function in individuals living with CP. Methods: Five databases were screened. The inclusion criteria were: (1) including people living with CP, (2) reporting measurements of upper limb motor and sensory functions. A qualitative analysis of the studies’ level of evidence was done. Results: Thirty-three articles were included. Twenty-five articles evaluated tactile functions, 10 proprioceptive functions and 7 visual functions; 31 of the articles reported on unimanual functions and 17 of them reported on bimanual functions. Tactile functions showed a moderate to high association; it was not possible to reach definitive conclusions for proprioceptive and visual functions. Conclusions: The heterogeneity of the results limits the ability to draw definitive conclusions. Further studies should aim to perform more comprehensive assessments of motor and sensory functions, to determine the relative contribution of various sensory modalities to simple and more complex motor functions. Performing upper limb movements, such as reaching for a glass and bringing it to one’s mouth, requires the integration of sensory information from various modalities . In the case of this example, vision provides information about the distance between the hand and the glass to grasp, as well as about the characteristics of the glass   which maCerebral palsy (CP) is a group of disorders mainly characterized by posture and movement deficits  includinAlthough hemiparetic CP is the most frequent type of CP , motor dThe aim of this systematic review is therefore to characterize the relationship between sensory deficits  and upper limbs motor functions (including UMF and BMF) in individuals with CP.https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=161016 (accessed on 1 June 2021).This systematic review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)  and was Five databases were screened: CINAHL, Medline, Web of Science, Embase, and PsycINFO. Systematic weekly alerts  for eachTo be included in the review, articles had to: (1) include individuals diagnosed with CP, regardless of the individuals’ age or CP type ; (2) report clinical or kinematic measurements of upper limb motor functions (UMF or BMF) and clinical assessments of sensory functions ; (3) present empirical data; and (4) be published through a peer-reviewed process. More specifically for the main outcomes (sensory and motor functions), articles had to meet at least one of three criteria: they had to (1) present associations between motor and sensory variables; (2) compare the motor performance of a group of individuals with CP who have sensory deficits, to that of individuals with CP who do not have sensory deficits; or (3) provide raw individual data that would make one of these analyses possible. This approach was used to include a maximum number of relevant articles. Studies reporting assessment of pain or temperature threshold have been excluded. Case studies, book chapters, meta-analyses, systematic reviews, conference abstracts, and articles written in languages other than English or French were also excluded. Titles and abstracts were screened independently by two reviewers (I.P. and O.M.) to identify their eligibility, and then, the selected articles’ full text was screened by these same reviewers to determine their eligibility. Article selection was discussed until consensus was reached and any disagreement was resolved by a third reviewer (C.M.).www.covidence.org (accessed on 1 June 2021) and consisted of: (1) participants’ characteristics ; (2) type of CP; (3) timing of lesion; (4) type of lesion; (5) sensory assessments; (6) sensory outcomes; (7) sensory modality ; (8) motor assessments; (9) motor outcomes; (10) type of motor functions (UMF or BMF); and (11) description of assessments and results.One author (I.P.) performed the data extraction for the 33 selected articles and then the second author (O.M.) corroborated the extracted results. Variables extracted were based on a standardized tool see  (Better 2), Beta coefficient (β), coefficient of regression, and percentage based on regression model. For the interventional studies, raw data from the baseline were extracted and correlation analysis (Pearson or Spearman correlations) were performed using IBM SPSS Statistics for Windows, Version 26.0 . Results were considered significant when p < 0.05. Correlation coefficient were ranked as follows: perfect = +/−1.0, strong = +/−0.7–0.99; moderate = +/−0.4–0.69; low = +/−0.1–0.39 and no correlation = <+/−0.1 [Two types of study design were retrieved from the screening: cross-sectional studies with correlational or regression analysis, and interventional designs with raw data of the baseline outcomes. Results extracted from the cross-sectional studies were correlation coefficient , square coefficient .Tactile perception—Location of stimulus: Identification of the specific location of a single stimulus applied on a part of the body.Tactile perception—Double simultaneous stimulation: Capacity to identify the part of the hand touched, when one stimulus is applied to both sides.Tactile perception—Temporal discrimination: Capacity to identify the timing at which a stimulus occurred. In this review, this refers to a temporal order judgement between two stimuli applied on the fingers.Tactile perception—Texture discrimination: Capacity to distinguish different types of texture, such as silky, soft, or rough.Tactile Functions: Processing of sensory inputs arising from different types of receptors located in the skin to distinguish texture, vibration, shape, or pressure (pain and temperature were not included in this review). Tactile functions were generally separated into two main categories: registration (stimulus detection) and perception  . In thisProprioceptive functions: Perception of upper limb position and movement, sense of tension, force, effort, or balance . More spVisual integrity: Includes the visual field , the visual acuity  and the presence of eye problems interfering with vision such as strabismus, nystagmus, or problems with fixation of moving objects.Visual perception: The brain’s ability to make sense of what the eyes see, such as visual closure, figure/ground, or visual attention.Visual anticipatory pattern: Ocular movements and gaze time in preparation of upper limb movements.Visual functions: Ability to see with the eyes  and brain processing (integration) of the object seen with the eyes .Visual iSensory functions were categorized into three modalities: tactile, proprioceptive, and visual. For each modality, various functions were assessed:Unilateral motor functions (UMF): This refers to activities performed using only one arm .Bilateral motor functions (BMF): This refers to activities performed using both arms simultaneously. Almost all daily living activities can be considered BMF, as they typically require coordination between both arms .Capacities such as joint mobility, strength and motor coordination are required to perform basic daily activities . For theTwo authors (I.P. and O.M.) independently rated the overall quality of each article included in this study, using the “Standard quality assessment criteria” from Kmet et al. . A calibEach criterion was evaluated on a scale of 2 . The scores were converted to a percentage and a five-level scale was used to characterize the article’s quality: very high quality = 90% and more (VHQ); high quality = 80 to 89% (HQ); moderate quality = 70 to 79% (MQ); low quality = 60 to 69% (LQ); very low quality = 59% or less (VLQ). A weighted Gwet’s coefficient was calculated for each item of the grid to evaluate the pre-consensus inter-rater agreement. The level of agreement was defined as: poor = <0.0, slight = 0.0 to 0.20, fair = 0.21 to 0.40, moderate = 0.41 to 0.60, substantial = 0.61–0.80, and almost perfect = 0.81 to 1.00 [Conclusions were separated by type of motor functions (UMF or BMF) and by sensory function evaluated . Due to the heterogeneity of assessments used and the characteristics of the population evaluated in each article, only a descriptive synthesis of the results was performed, rather than full a meta-analysis.Strong evidence: Multiple high quality studies with consistent results.Moderate evidence: Multiple studies including at least one high quality study, or multiple moderate quality or low quality studies presenting consistent results.Conflicting evidence: Multiple studies providing inconsistent results, regardless of methodological quality.Limited evidence: Multiple moderate quality or low quality studies with inconsistent results, or only one high quality study.Very limited evidence: Only one low quality or moderate quality study.The level of evidence was characterized by integrating four domains of concerns: (1) number of studies and participants (imprecision); (2) methodological quality (risk of bias); (3) similarities in methodological setting and outcomes (indirectness); and (4) direction of results (inconsistency). An adapted scale has been used in accordance with the type of protocol, and has been used to characterize the level of evidence for sensory and motor function as follows :Strong eThe database search strategy yielded 6711 articles, to which two articles were added by manually searching through references. After removing the duplicates, processing titles/abstracts and screening the full texts, 33 articles were included in this review see , represeKmet and Lee’s Standard quality assessment  criterian = 5) and objective measurements . The study’s results for both UMF and BMF are presented according to targeted functions in the following order: tactile, proprioceptive, and visual functions. Tactile pressure detection was assessed in eight of the articles in relation to UMF [n to UMF ,60,64,67n to UMF ,44,60,67n to UMF ,44 reporn to UMF ,60,67, mTactile vibration was assessed in only one high quality article in relation to UMF [p < 0.01) for a piano-related task.n to UMF . As a reTwo-point discrimination was assessed in 13 of the articles in relation to UMF [p < 0.05) between two-point discrimination and BMF, with only one article [n to UMF ,66,67,72n to UMF ,65,66,67Stereognosis was assessed in 17 of the articles in relation to UMF [n to UMF ,66,67,71n to UMF ,65,66,67n to UMF  and the n to UMF . ResultsGraphesthesia was assessed in three of the articles in relation to UMF [n to UMF ,65,72 anDirectionality of stimulation was assessed in three of the articles in relation to UMF [n to UMF ,49,71. TLocation of stimulus was assessed in six articles for UMF [ for UMF ,63,65,72 for UMF ,59,65. R for UMF . For BMFDouble simultaneous stimulation was assessed in three articles in relation to UMF [n to UMF ,63,72 ann to UMF . LimitedTemporal discrimination was assessed in one high quality article evaluating UMF [ting UMF . This arTexture discrimination was assessed in two articles in relation to UMF [n to UMF ,51 and in to UMF . ResultsOverall, studies on tactile functions show evidence of moderate to strong association between both two-point discrimination and stereognosis and UMF and BMF, although the evidence remains somewhat conflicting for the association between two-point discrimination and UMF. Other variables received limited attention, and evidence is therefore either limited or conflicting, making it impossible to reach a clear conclusion within the scope of this study.Proprioception was addressed in nine articles with respect to UMF [t to UMF ,72,73,74t to UMF ,59,69,73Overall, there is conflicting evidence about the association between UMF or BMF and proprioceptive functions.Vision integrity  and visual anticipatory patterns were assessed in only one study of low quality [ quality  and one  quality , respectVisual perception was assessed in four articles in relation to UMF [n to UMF ,47,56,63n to UMF , which lOverall, the results support the presence of a moderate to high association between visual functions assessed and motor functions (either UMF or BMF). However, evidence remains limited due to the small number of high quality studies .This systematic review allows us to conclude that stereognosis and two-point discrimination are both positively associated with motor functions (either UMF or BMF). Other tactile functions have shown conflicting or very limited evidence of association with either UMF or BMF, reflecting the importance of assessing these variables in future studies to clarify their potential contribution to motor impairments. The same conclusion applies to proprioceptive functions, as the heterogeneity across existing studies included in this review makes it impossible to reach a definitive conclusion. A positive association between visual and motor functions has been observed, but the very limited number of high quality studies restrict the strength of this conclusion, especially for vision integrity. First, we will discuss some disparities between the results obtained for UMF and BMF, as to the best of our knowledge this review is the first attempting to synthetize the evidence on the association between BMF and sensory functions. Second, the results of each type of sensory function will be discussed separately . Third, whether the observed associations reflect causal relationships or not will be addressed. Finally, the study limitations and risk of bias will be discussed.The level of association between sensory functions and BMF appears to be generally similar to that observed with UMF, although studies were generally not designed to address this question directly. The small disparities observed between UMF and BMF conclusions are likely to be explained in part by the type of motor assessments  and the number of high quality studies included for each motor function (which was lower for BMF) . AnotherFor tactile functions specifically, a previous review by Bleyenheuft and Gordon  providedThe evidence of an association between proprioceptive and UMF or BMF functions is conflicting, with a limited number of studies addressing BMF. However, the association between proprioception and motor functions  has beenUltimately, evidence is too scarce for definitive conclusions on the association between visual and motor functions , but is generally supportive of the presence of an association. The importance of vision for motor planning , motor Study Limitations: The heterogeneity in population characteristics limits the possibility to generalize results: only a few studies reported the classification of impairment level or presented subgroup analyses according to type of CP or individuals’ age. Identification of the MACS and GMFCS would have made it possible to determine whether the samples of studies included in this review are representative of the population of people living with CP. Furthermore, the use of a mix of participants with various anatomical distribution of CP  in the same article could have contributed to the heterogeneity of the results. However, these characteristics were taken into consideration during the methodological assessments, leading to a lower methodological score and less weight being given in the analysis process. The wide range of ages covered by the articles (sometimes ranging from young children to adult participants within the same study) weakened the conclusions by neglecting to consider the developmental stage of the participants in their interpretations. Bleyenheuft and al.  recommenRisk of Bias: Eighty percent (26 out of 33 studies) of the included articles were rated as moderate to very high quality studies, which suggests a low risk of bias. Two articles were also excluded because they were written in a language other than English or French, which adds a small risk of bias. The Gwet coefficient is high (interrater reliability coefficient = 0.969). For all of these reasons, the risk of bias for this systematic review is considered to be very low.This systematic review aimed to provide a comprehensive summary of the current evidence related to associations between sensory and motor functions. The level of association between sensory and motor functions was found to vary across the sensory functions evaluated. Stereognosis and two-point discrimination are the two functions that were quite systematically found to be associated with motor functions. While there are some results supporting the associations with proprioception and visual perception as well, evidence is still lacking and there is still considerable heterogeneity across the studies. Further studies should consider additional variables, such as neurological variables , type of CP and the potential effects of age. Special attention should also be paid to the type of assessments used to assess motor function, since these often focus on different types of tasks  or motor capacities . In addition, since the majority of articles report data for one type of sensory input only, more comprehensive assessments  would help us understand the relative contribution of each sensory modality to simple and more complex motor functions. Finally, evaluating the impact of sensory functions on the use of each upper limb in the context of everyday activities (for instance quantified through accelerometry) would provide a complementary perspective on the contribution of sensory functions to motor performance.


Introduction: Studies of brain-damaged patients revealed that amygdala lesions cause deficits in the processing and recognition of emotional faces. Patients with autism spectrum disorders (ASD) have similar deficits also related to dysfunctions of the limbic system including the amygdala.Methods: We investigated a male patient who had been diagnosed with Asperger's syndrome. He also presented with a lesion of the right mesial temporal cortex, including the amygdala. We used functional magnetic resonance imaging (fMRI) to investigate neuronal processing during a passive viewing task of implicit and explicit emotional faces. Clinical assessment included a facial emotion recognition task.Results: There was no amygdala activation on both sides during the presentation of masked emotional faces compared to the no-face control condition. Presentation of unmasked happy and angry faces activated the left amygdala compared to the no-face control condition. There was no amygdala activation in response to unmasked fearful faces on both sides. In the facial emotion recognition task, the patient biased positive and neutral expressions as negative.Conclusions: This case report describes a male patient with right amygdala damage and an ASD. He displayed a non-response of the amygdala to fearful faces and tended to misinterpret fearful expressions. Moreover, a non-reactivity of both amygdalae to emotional facial expressions at an implicit processing level was revealed. It is discussed whether the deficient implicit processing of facial emotional information and abnormalities in fear processing could contribute and aggravate the patient's impairments in social behavior and interaction. The competence to recognize emotional facial expressions and to interpret social interaction, including empathy abilities, is critical for social communication. Neuroimaging studies have provided evidence of different brain regions being responsible for facial emotion recognition  to investigate neural response of the amygdala during explicit and implicit processing of different emotions, using a facial recognition tasks on a patient with early damage of the right amygdala and Asperger's syndrome. Our aim was to investigate the combined effect of cerebral damage and ASD on emotional face recognition and processing. The amygdala may form an important part of the pathogenic substrate of ASD, but it remains to be further clarified whether ASD individuals are characterized by heightened or reduced amygdala reactivity to emotional, and in particular fearful, facial expressions.St. is a 34-year-old technician who had initially been admitted to a neurological unit because of deficits in concentration and alertness as well as recurrent alterations of consciousness. Neurological examination was normal and EEG revealed no abnormal brain waves. MRI showed a contrast medium accumulating temporo-mesial tumor, a lesion temporo-basal on the right side (22 × 6 × 12 mm) see . The radAccording to his parents, his birth had been normal, but early in development, the patient showed abnormal behavior such as an excessive interest in technical matters. In school, the patient revealed mathematical skills above age-average, but failed in foreign languages or practical language use. Social behavior had always been abnormal; the patient had no close friends. He passed high school with an average degree and, afterwards, worked as a technician. The patient was discharged from his last employment, because he displayed concentration deficits and aggressive behavior with increasing frequency when under pressure. He had few varying facial expressions, body postures and gestures to regulate social interaction, and had difficulties developing peer relationships. He showed a stereotyped and restricted pattern of interest that was abnormal in its intensity (electric agents). He was lacking social and emotional reciprocity, could not keep himself aloof, and his sense of humor was reduced. The symptoms could not be explained by depressive mood only, since most symptoms started early in development. St. met criteria for an Asperger's syndrome APA, .St. received 2.5 mg olanzapine and 40 mg ziprasidone at the time of testing. He had no history of substance abuse or dependence and no severe somatic disorders. The patient had no chromosomal abnormalities. His visual impairment was sufficiently corrected (Snellen eye chart). St. gave written informed consent to the experiment. It was approved by the Ethics Committee of the Medical Faculty of the University of Muenster and the Medical Association of Westphalia-Lippe and was carried out in accordance with the Declaration of Helsinki. St.'s co-operation throughout the testing sessions was good, he was very motivated. His mood was stabilized at the time of testing. St. was right-handed; handedness was defined by the Edinburgh Handedness Questionnaire  developed by Ekman and Friesen . The PFAIn our fMRI experiment, we administered pictures with angry, fearful, happy, and neutral emotional expressions (10 pictures per expression condition). All pictures were presented repeatedly. The patient was presented with alternating 30 s epochs of masked fearful, masked angry, masked happy, and neutral faces or a no-face control stimulus (a gray rectangle). Within epochs, masked stimuli were presented twice per second in a random sequence. Each trial had a duration of 500 ms. In masked face trials, a fearful, angry, or happy expression was presented for 33 ms, followed immediately by a 467 ms neutral expression. In the unmasked face trials of our experiment, angry, fearful, happy, and neutral facial expressions were shown for 500 ms. The no-face control stimulus was shown for 450 ms, followed by a blank screen for 50 ms. There was a counterbalanced order of presentation (Latin square design). Thus, each face epoch was preceded by a no-face control epoch and was presented twice, so that the overall presentation time was 8 min  160 times in a block design, 10 times per condition.fMRI data were obtained while the patient was lying supine in the MR scanner tunnel. Images were projected (Sharp XG-PC10XE projector) onto a screen at the rear of the scanner tunnel which could be viewed through a mirror (8 × 12 cm) mounted at the MR head coil. Image presentation was realized by means of the software package Experimental Run Time System . fMRI data were motion-corrected, in a first analysis coregistered to the anatomical dataset and in a final analysis, spatially normalized to standard MNI space  and smoothed (6 mm FWHM) using Statistical Parametric Mapping . Statistical analysis was performed by modeling the different conditions  as variables within the context of the general linear model (modeled by a standard hemodynamic response function) on a voxel-by-voxel basis.http://www.fmri.wfubmc.edu/cms/software, version 3.0) . As on this strict threshold no significant results were yielded, we applied a statistical threshold of p < 0.001, uncorrected.Region of interest (ROI) analysis was performed using anatomically defined ROIs for both amygdalae (left and right) using the SPM Wake Forest University (WFU) Pickatlas toolbox . He was asked (1) to decide whether he had seen the expressions on the faces during the scanning period . Task (2) was an emotion recognition/identification task. Here, the patient had to identify which emotion each face displayed (whether seen or not) and was encouraged to choose between all of the above-mentioned emotions on a list .On the quotients by Baron-Cohen, he scored 31 points on the EQ (low empathy), 38 points on the SQ (average), 27 points on the AQ (autistic traits over average).X = −18, Y = 0, Z = −12, df = 294, T = 5.19, Z-score, = 5.08, cluster size 11, p uncorr. < 0.001) .Neither the coregistered nor the normalized data revealed activation in the amygdala on the side of the lesion in response to any of the stimuli. Also, no activation of either amygdala was identified in response to masked emotional stimuli or fearful stimuli in the unmasked condition. Moreover, in the unmasked condition, ROI analyses revealed a unilateral activation of the left amygdala on the contrast of angry vs. no-face condition (001) see  as well In the discrimination task, St. identified 31 out of 50 stimuli correctly, i.e., he named the facial identity with the emotion it displayed correctly as “seen” or “not seen” during the scanning session. The results of the facial stimuli he falsely identified are shown in In the emotion recognition task, St. named 30 out of 50 facial emotions correctly. He recognized all sad faces and nearly all happy faces. He had great difficulties recognizing neutral faces, identifying them falsely as “sad” in 10 out of 20 cases. In addition, in many cases angry faces were misjudged as “sad” (2 out of 8) or “disgusted” (4 out of 8), while two out of four fearful faces were also falsely identified as “disgusted.” For details, see In this single case study on a right amygdala lesion in an Asperger's syndrome patient, we comprehensively investigated implicit and explicit emotion recognition of faces using fMRI. The patient displayed severe deficits in emotion recognition on a behavioral level with a tendency to misinterpret neutral or angry faces.As we here present a single-case report, results of healthy and ASD individuals without brain damage need to be compared. In a young healthy sample (age 20–40 years), stimuli taken from the Facial Expressions of Emotion Stimuli and Tests  in the scanner, such an instruction should have promoted attentive behavior. This can also be deduced from his recognition performance. Another point is whether psychopharmacological treatment at the time of testing might have had an effect on the patient's performance. Our patient received antipsychotic as well as antidepressive medication at the time of the testing, which might both have affected cognitive performance. However, research shows that antipsychotic and antidepressive medication have a beneficial or non-significant effect on cognition, at least in patient groups that regularly take antipsychotics  for the publication of any potentially identifiable images or data included in this article.KK: conception, writing of draft, correspondence, data collection and analysis, and testing JB: conception, data management, data analysis, technical support, and writing the draft TS: testing, conception, providing the paradigm, writing the draft, and data analysis PO: conception, testing, and writing the draft. All authors contributed to the article and approved the submitted version.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.


Urinary stones cause hydronephrosis, which leads to kidney function impairment. The serum creatinine level is frequently used as a marker of kidney function. However, in some patients with hydronephrosis, it does not reflect the kidney function changes in the early stages of kidney stone disease. Neutrophil gelatinase-associated lipocalin (NGAL) is a novel indicator of the kidney function. Previous NGAL-related research has focused on its role in acute kidney injury. This study aimed to determine the usefulness of NGAL as an early marker of the kidney function in patients with urinary stones and hydronephrosis.Eighty-five patients with urinary stones who were admitted to the Shanghai Tenth People's Hospital (USP group) and 65 healthy volunteers (NC group) were recruited. Blood and urine samples collected from the study participants were evaluated using an enzyme-linked immunosorbent assay to determine the NGAL concentration. Data on the height, weight, age, medical history, and blood and urine findings were collected. Computed tomography data were collected from the USP group.P < 0.001). However, no significant differences in the NGAL levels were observed among the USP group members with different degrees of hydronephrosis. Furthermore, no significant between-group differences in the creatinine level or the estimated glomerular filtration rate were observed. The areas under the receiver operating characteristic curves for the serum and urinary NGAL levels with hydronephrosis were 92.03 and 99.54%, respectively. The areas under the receiver operating characteristic curves for the serum and urinary NGAL levels with kidney stones were 85.05 and 91.89%, respectively.Compared to in the NC group, NGAL levels were significantly elevated in the USP group (NGAL is a sensitive indicator of hydronephrosis secondary to urinary stones. Urinary stone disease is very common . UrinaryCurrently, serum creatinine level is one of the main markers of kidney function –8. CreatIn Kjeldsen et al.  discoverMany diseases affect kidney function; however, most do not do so as quickly as AKI. Nonetheless, early detection of kidney function remains important . CurrentIn this study, 85 patients who were hospitalized at the Tenth People's Hospital of Tongji University (between July 2020 and December 2020) for urinary stones were enrolled and categorized into the USP group. In addition, 65 volunteers who underwent an ultrasound examination of the urinary system to rule out the possibility of hydronephrosis and urinary stones were enrolled as healthy controls in the NC group. We took the short diameter of the renal pelvis cavity under ultrasound as greater than 1 cm as the standard for hydronephrosis. The following inclusion criteria were applied: no history of diseases that may impair renal function, such as hypertension and diabetes; no history of acute or chronic renal impairment; no history of kidney surgery; and first identification of kidney stones and hydronephrosis. Patients with urolithiasis underwent Computed Tomography (CT) and the CT data were collected. The following data were collected from the study participants: age, weight, height, eGFR, and medical history. The body mass index (BMI) for each participant was also calculated from their height and weight. This cohort study was following STOBE guidelines and approved by the ethics committee of Shanghai Tenth People's Hospital (approved number was 21K105), and informed consent was obtained from all patients who participated in the study.From each participant, 2 mL of blood and 5 mL of urine were collected for further analysis. The blood samples were allowed to stand at room temperature for 2 h; they were then centrifuged, and the serum was extracted. The serum and urine samples were stored at −80°C for future analysis. Serum creatinine and urea nitrogen levels were measured at the Central Laboratory of the hospital. The serum and urinary NGAL concentrations were measured using the Human NGAL/Lipocalin-2 ELISA Kit .t-test were used to perform the intergroup comparisons. If the measurement data did not follow a normal distribution, the medians (interquartile ranges) and the rank-sum test were used to perform the intergroup comparisons. Count data were compared using the chi-square test. Statistical significance was set at p < 0.05.Statistical analyses were performed using the SPSS 16.0 statistical package, and charts were made using GraphPad Prism 7. If the measurement data were normally distributed, means and standard deviations and the P < 0.001) and urinary NGAL level . However, no significant between-group differences were observed in the sex , height , weight , BMI , serum creatinine levels , serum urea nitrogen concentrations , CKD-EPI (NC 92.30 ± 23.82 mL/(min*1.73 m2), USP 89.36 ± 23.23 mL/(min*1.73 m2), P-value 0.451). The characteristics of the study participants are summarized in Compared with the NC group , the USP group had significantly elevated serum NGAL level  are shown in P < 0.001). However, there were no significant differences in the serum/urinary NGAL levels among the USP subgroups , moderate hydrops group (USP2), and severe hydrops group (USP3). Results indicated significant differences in the serum and urinary NGAL levels between the healthy control group and each USP group  and 99.54% , respectively. For kidney stones, the areas under the ROC curve for the blood and urine NGAL levels were 85.05%  and 91.89% , respectively (A receiver operating characteristic (ROC) curve of the serum and urinary NGAL levels with hydronephrosis and kidney stones was created. Results indicated that for hydronephrosis, the areas under the ROC curve for the blood and urine NGAL levels were 92.03%  in the kidneys. It is a common disease that occurs more frequently in men than in women, and is particularly predominant in young men. Stones can occur in any part of the urinary system, but their formation often initiates in the kidneys. Kidney stones tend to be located in the renal pelvis or calyces, and can be discharged to the ureter or bladder , 27. NeaAt the same time, we also note that there are some limitations in this study. Since this is the first time we have conducted a cohort study on the clinical significance of NGAL in the diagnosis of hydronephrosis caused by urinary calculi, the sample size of this study is small, the detection of urine creatinine level is lacking, and the analysis of NGAL and prognosis in patients with urinary calculi is lacking. We will further improve it in the follow-up cross-sectional study.NGAL is a very sensitive indicator of hydronephrosis caused by urinary stone.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Ethics Committee of Shanghai Tenth People's Hospital. The patients/participants provided their written informed consent to participate in this study.TX, XH, and YX: conception and design. HZ, YG, XX, and XH: data acquisition. HZ and YG: analysis and interpretation of data. TX, HZ, YG, and XX: statistical analysis. XX: drafting of the manuscript. XY: revision of the manuscript. YX: supervision. All authors contributed to the article and approved the submitted version.This study was funded by National Natural Science Foundation of China (Nos. 81971371 and 82101671) and 2019 Scientific Research Funds of Shanghai Tenth People's Hospital (No. 04.03.19.043).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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The Hippo pathway is an essential signaling cascade that regulates cell and organ growth. However, there is no consensus about (i) the expression levels of the Hippo signaling core components yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) in lung cancer, especially in small cell lung cancer (SCLC), or (ii) their association with the prognosis of patients with SCLC.We screened relevant articles and identified eligible studies in the PubMed, EMBASE, COCHRANE, and WanFang databases. A combined analysis was performed to investigate (i) the expression levels of the major effectors, YAP and TAZ, in lung cancer and its subsets and (ii) their prognostic role in lung cancer, especially in SCLC.Ph < 0.001, crude hazard ratio (HR) = 1.629, 95% CI = 1.199–2.214 for TAZ expression; Ph = 0.029, adjusted HR = 2.127, 95% CI = 1.307–3.460 for TAZ], the Caucasian population , and the Asian population . Moreover, there was a significant negative association between YAP expression and an unsatisfactory survival of patients with lung cancer  and patients with NSCLC , especially in the Asian population . However, no association was observed in the multivariate combined analysis. High YAP expression was significantly associated with short OS of patients with SCLC in our combined multivariate analysis in the Asian population , but not with crude data .In total, 6 studies related to TAZ and 13 studies concerning YAP were enrolled in this meta-analysis. We found that high TAZ expression was significantly associated with poor overall survival (OS) of patients with non-small cell lung cancer (NSCLC) in the overall population [The Hippo pathway is involved in carcinogenesis and progression of NSCLC and SCLC, and high expression levels of YAP and TAZ are independent and novel prognostic factors for lung cancer. Lung cancer is a primary malignancy with one of the highest rates of morbidity and mortality in China . Accordivia participation in multiple cancer-related processes, including cancer cell growth, migration, and distal metastasis in various malignancies, such as colorectal, gastric, and lung cancer  and transcriptional co-activator with PDZ-binding motif (TAZ) are transcription co-activators and the core downstream effectors of the Hippo signaling pathway . When thg cancer –8.EGFR)-mutant NSCLC treated with first-line EGFR tyrosine kinase inhibitors  guidelines . First, The following clinical baseline characteristics were extracted from each study: the first author's name, study design, country, race, recruitment time, disease, number of included cases, treatment, outcome, HR, and 95% CI. All data were rechecked.2 were selected to evaluate the heterogeneity of included studies in this meta-analysis, where Ph < 0.1 or I2 > 50% was considered to indicate substantial heterogeneity. The combined analysis of eligible studies was assessed by the Z test based on a fixed (Ph > 0.1) or random (Ph < 0.1) model. Publication bias within the included studies was evaluated by funnel plots , the Caucasian population , and the Asian population .The combined HR and 95% CI of TAZ expression and overall survival (OS) of patients with NSCLC are described in Ph = 0.327, I2 = 13.6%, crude HR = 1.652, 95% CI = 1.211–2.253) . The significant negative association between YAP expression and survival of patients with NSCLC was also observed in the overall population  and the Asian population . Moreover, high YAP-mRNA was also significantly associated with the survival of patients with NSCLC . However, no association between them was observed in the multivariate combined analysis. High YAP expression was significantly associated with short OS of patients with SCLC in our combined multivariate analysis in the Asian population , but not with the crude data   ; Table 34–6.300) ; Table 3In our study, relatively symmetric funnel plots were observed in our prognostic comparisons of patients with high- and low-TAZ NSCLC. Moreover, symmetric funnel plots were also found in the combined survival analysis of the patients with high- and low-YAP lung cancer, NSCLC, and SCLC .The association of YAP and TAZ expression and lung cancer survival, particularly in patients with SCLC, remains unclear. This meta-analysis revealed that TAZ is significantly associated with poor OS of patients with NSCLC in the overall population and the Asian population. Moreover, a significant association was observed between high YAP expression and unsatisfactory survival of patients with lung cancer and patients with NSCLC, especially in the Asian population. However, no association between them was observed in the multivariate combined analysis. YAP expression was significantly associated with short OS in our combined analysis in the Asian SCLC population based on multivariate data, but not crude data.Lung cancer is a complex and challenging disease that interacts with environmental and genetic factors . Many siThree meta-analyses reported the predictive role of YAP in clinical outcomes in various cancers –40. TheyTo the best of our knowledge, this meta-analysis used the largest sample size to date to analyze the prognostic roles of TAZ and YAP in lung cancer and patients with NSCLC. In addition, this is the first study to report the role of YAP in the prognosis of patients with SCLC. However, there are several limitations to this study. First, no studies on the association between TAZ expression and survival of patients with SCLC were included, so the prognostic role of TAZ in SCLC remains to be elucidated. Second, the sample size of included studies related to YAP expression in patients with SCLC was small. Our findings should be validated by multi-center clinical trials with larger sample sizes. It is also important to emphasize that most studies were conducted in the Asian population. Third, patients with different TNM stages and various treatment options were enrolled in each study. These factors might influence the combined results and hence, the results should be validated by prospective studies with patients with NSCLC or SCLC in specific TNM stages. Fourth, different expression models of YAP or TAZ, different detection methods, and different genetic backgrounds of the patients enrolled in the included studies might lead to inconsistent results.YAP and TAZ function as oncogenes in both NSCLC and SCLC and aberrant protein expression levels of YAP and TAZ are independent and novel prognostic factors for these diseases. Further studies are warranted to validate the findings in the Asian population and explore effective biomarkers to predict the prognosis of patients.In summary, YJ is responsible for the concept or design of the work. W-JX and R-WC are responsible for data collection. W-LY and HC are responsible for drafting the article. W-XC and J-PX are responsible for making important revisions to the article. All authors contributed to the article and approved the submitted version.The study was supported by the Fujian Provincial Natural Science Foundation (2018J01360).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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Introduction: Neuropsychiatric symptoms in patients with frontotemporal dementia (FTD) are highly prevalent and may complicate clinical managements.Objective: To test whether the Neuropsychiatry Inventory (NPI) could detect change in neuropsychiatric symptoms and caregiver's distress in patients diagnosed with behavioral variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD) from baseline to a 12-month follow-up and to investigate possible predictors of change in NPI scores.Methods: The sample consisted of 31 patients diagnosed with bvFTD and 28 patients with AD and their caregivers. The Mini-Mental State Examination (MMSE), Addenbrooke's Cognitive Examination Revised (ACE-R), the INECO Frontal Screening (IFS), the Frontal Assessment Battery (FAB), the Executive Interview (EXIT-25) and the NPI were applied. Descriptive statistics, Mann-Whitney U test, Wilcoxon test, Chi square (χ2) test and Linear Regression Analysis were used.Results: NPI total and caregiver distress scores were statistically higher among bvFTD patients at both assessment points. MMSE, ACE-R scores significantly declined and NPI Total and Distress scores significantly increased in both groups. In the bvFTD group, age was the only independent predictor variable for the NPI total score at follow up. In the AD group, ACE-R and EXIT-25, conjunctively, were associated with the NPI total score at follow up.Conclusions: In 12 months, cognition declined and neuropsychiatric symptoms increased in bvFTD and AD groups. In the AD group only, cognitive impairment was a significant predictor of change in neuropsychiatric symptoms. Behavioral variant frontotemporal dementia (bvFTD) is a neurodegenerative syndrome which is usually diagnosed in midlife (mean age at onset around 58 years). Prevalence peaks in the early sixties, at about 13 cases per 100,000 individuals. Among the frontotemporal dementias, bvFTD is the most common one as it represents 50% of the cases , Kumfor et al.  reportedClinical studies with follow-up data regarding neuropsychiatric symptoms in bvFTD and possible predictors of change are lacking . TherefoQuestions about age, sex, and years of education were answered by the caregivers.University-based neurology outpatient services databases were queried, and patients and their family caregivers were recruited for the study. Specialized dementia centers across three Brazilian universities were involved: the Cognitive and Behavioral Neurology Group (GNCC-SP) and the Program for the Elderly (PROTER) at the University of São Paulo; the Cognitive and Behavioral Neurology Group (GNCC-MG) at the Federal University of Minas Gerais and the Department of Neurology at the State University of Campinas (UNICAMP).A total of 59 individuals, comprising 28 diagnosed with AD and 31 with bvFTD, were included in the study. Patients with bvFTD and with AD were matched for disease severity on the Clinical Dementia Rating scale–frontotemporal lobar degeneration , wiThe diagnosis of bvFTD and AD was performed by neurologists, geriatricians and psychiatrists, based on clinical, neurological history, neuropsychological assessments and screening for reversible causes of dementia along with laboratory and neuroimaging exams: functional Magnetic Resonance Imaging (fMRI) and Fluorodeoxyglucose PET (FDG-PET patterns). Dementia was diagnosed based on the criteria from the Diagnostic and Statistical Manual 5th Edition . InternInclusion criteria for patients were age ≥40 years, education > 2 years and the presence of an informant who was involved in the daily routine of the patient . Individuals presenting with visual, auditory or motor deficits preventing them from understanding instructions or performing cognitive tasks, individuals with other uncontrolled clinical diseases (such as hypertension and diabetes), serious and debilitating psychiatric disorders such as major depression, schizophrenia, bipolar disorder, clinical evidence or neuroimaging exam findings suggestive of vascular problems, dementias or etiologies other than bvFTD or AD, were excluded.General cognition was assessed with the MMSE (0–30 points) , 16) a a16) andExecutive functions were assessed with the INECO Frontal Screening (IFS) (0–30 points), the Frontal Assessment Battery (FAB) (0–18 points) and the Executive Interview (EXIT-25) (0–50 points). The IFS items assess: response inhibition and set shifting , abstraction (proverb interpretation) and, working memory . The IFS generates a separate score for working memory which varies from 0 to 9 , 20. TheThe NPI assesses neuropsychiatric symptoms commonly found in dementia. It evaluates 12 domains ; thus yielding a composite symptom domain score  (frequency × severity) ranging from 0  to 144 points  . The sca2) test, Mann-Whitney U test and Wilcoxon test.Initially, all quantitative variables (continuous and discrete) were analyzed using the Kolmogorov-Smirnov test to assess whether or not they followed a normal distribution. The absence of normal distribution was observed in most quantitative variables, so non-parametric tests were used: Chi-square , from the simplest to the most complex model .p-value < 0.05.The computer program Statistica 7.0 was used. The level of significance adopted for the statistical tests was 5%, that is, This study was approved by the Ethics Committee of the Hospital das Clínicas, protocol number 311.601. The study was conducted in compliance with international ethical standards, according to the Declaration of Helsinki.The demographic and clinical characteristics of the patients are presented in Patients with AD were significantly older than the patients with bvFTD. MMSE and ACE-R scores decreased significantly from baseline to follow-up in both clinical groups. EXIT-25 scores significantly declined for the bvFTD group only, indicating that the executive dysfunction may have increased over time in this group. IFS and FAB scores remained unchanged for both groups . NPI TotFor a better graphical display of the NPI results, a radar chart was used . In thisWhen the clinical groups were compared at baseline, significant differences emerged, as higher scores can be seen for the bvFTD group for: agitation, eating disturbances and disinhibition ; Table 2The groups were significantly different at baseline and follow-up, with higher scores for the bvFTD group, in NPI agitation, disinhibition, and eating disturbances, see We did not find significant correlations between NPI data and cognitive variables. However, using the Linear Regression Analysis, as seen in The aim of the present study was to test the hypothesis that there was significant change in neuropsychiatric symptoms, assessed by the NPI, in patients with bvFTD and AD, from baseline to the 12-month follow-up. We also investigated if there were changes in the NPI Caregiver Distress score and explored potential links between sociodemographic variables, cognitive performance and neuropsychiatric symptoms at baseline and follow-up. The groups were statistically similar in terms of sex, education, cognitive and functional assessment scores. The mean age was higher in the AD group. The clinical groups differed from the start in terms of NPI Total and Distress scores (bvFTD > AD).In the present study, after 12 months, both groups presented with a reduction in MMSE and ACE-R scores and an increase in the NPI Total and Distress scores. An increase in executive dysfunction was also observed, according to the EXIT-25 scores, in the bvFTD group.Neuropsychiatric symptoms  were statistically higher among bvFTD patients. Separately, agitation, disinhibition and eating disorders symptoms were higher in the bvFTD group, at baseline and follow-up assessments. Hallucination, agitation and irritability were higher in bvFTD at follow-up assessment in NPI Distress. These data confirm previous studies results , 28 as tNot many studies have looked at differences between dementia subtypes in clinic-based samples using the NPI. In the first study that looked at differences in the NPI between AD and bvFTD, disinhibition, euphoria, apathy and aberrant motor behavior were found to be significantly higher in FTD . The samIn a recent study, with bvFTD, AD patients, and primary progressive aphasia (PPA) patients, Radakovic et al.  used theLiu et al.  suggesteThere is limited information regarding the trajectory of neuropsychiatric symptoms over time in AD and bvFTD. Present results suggest there was significant worsening in NPI  in both groups. For some NPI domains, group differences reached significance at follow up, with worse scores in the bvFTD group, which suggests changes in NPI scores were of higher magnitude in this group. These results, in a short follow up period, suggest that it is relevant to track changes in neuropsychiatric symptoms over time, to better caregivers regarding care challenges. Higher emotional overload may be present in bvFTD patients' caregivers, due to behavior and personality changes, as assessed with the NPI scale . AdditioFinally, we highlight that neuropsychiatric symptoms in AD only were associated with cognitive scores in the regression analyses. This finding may perhaps be explained by the fact that cognitive impairment is a core symptom in AD since the early disease stages and, therefore, cognition may drive neuropsychiatric symptoms.As to study limitations, we cite that the present study was based on relatively small samples, and this may have hindered the identification of group differences of small magnitude. As to its strengths, we indicate the inclusion of a follow up assessment.Due to the epidemiological significance of bvFTD, further research studies on the clinical characterization of the disease course are needed. Research studies with larger samples, including different dementia subtypes, examining the links between cognitive performance, neuropsychiatric symptoms and caregiver burden are recommended.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by the Ethics Committee for Analysis of Research Projects (CAPPesq) of the Medical Board of the Clinics Hospital and of the University of São Paulo School of Medicine, protocol number 311.601. The study was conducted in compliance with international ethical standards (Declaration of Helsinki). The patients/participants provided their written informed consent to participate in this study.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.This project was supported by the São Paulo Research Foundation (FAPESP) Grant Number: 11/04804-1 and 16/07967-2. Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Grant Number: 151684/2014-6 and by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Grant Number: 88881.131619/2016-01.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Monitoring microclimate variables within cities with high accuracy is an ongoing challenge for a better urban resilience to climate change. Assessing the intra-urban characteristics of a city is of vital importance for ensuring fine living standards for citizens. Here, a novel mobile microclimate station is applied for monitoring the main microclimatic variables regulating urban and intra-urban environment, as well as directionally monitoring shortwave radiation and illuminance and hence systematically map for the first time the effect of urban surfaces and anthropogenic heat. We performed day-time and night-time monitoring campaigns within a historical city in Italy, characterized by substantial urban structure differentiations. We found significant intra-urban variations concerning variables such as air temperature and shortwave radiation. Moreover, the proposed experimental framework may capture, for the very first time, significant directional variations with respect to shortwave radiation and illuminance across the city at microclimate scale. The presented mobile station represents therefore the key missing piece for exhaustively identifying urban environmental quality, anthropogenic actions, and data driven modelling toward risk and resilience planning. It can be therefore used in combination with satellite data, stable weather station or other mobile stations, e.g. wearable sensing techniques, through a citizens’ science approach in smart, livable, and sustainable cities in the near future. Urbanization is typically followed by high population and building density and consequent land-use and surface alterations, e.g. deforestation, loss of farmland3. Natural-to-urban land alterations affect in turn the local energy balance of cities and thus their microclimatic characteristics and thermal environment in particular5. As a result, cities tend to systematically experience higher surface and air temperatures as compared to the surrounding rural areas, a phenomenon reported as Urban Heat Island (UHI) effect9. The driving physics behind UHI is the reduction in latent heat flux and increase in sensible heat flux11. UHI is a significant human-induced environmental change that poses threats to human life. For instance, increased morbidity and mortality12, indoor/outdoor discomfort13, air pollution15, increased energy consumption16 and greenhouse gas emissions18, impaired air and water quality19 and intensification of energy poverty on vulnerable social groups during the hot months of the year21 are just some of UHI consequences that usually are interconnected. Also, UHI is associated with global warming and moreover has been found to synergistically act with heatwaves and amplify their impacts24. Considering the projections linked to the ongoing climate change, the livability of cities will be seriously endangered25. In fact, according to IPCC’s Representative Concentration Pathway (RCP) 8.5, global warming is expected to reach up to 1.5° above pre-industrial levels by 2050, and up to 2.0°–4.9° by 2100 as compared to 1861–188027. Thus, heat-related risk within urban canopy layers is likely to increase even more in the very near future, making the urban population particularly vulnerable during periods of hot weather.Within recent decades the rural-to-urban population flow has substantially increased. In 2016, 54% of the world population was reported to live in urbanised areas. At the same time, future projections of urbanization rates are rather alarming. It is expected that by 2050 and 2100 the corresponding fraction will increase up to 66% and 85% respectively32. Quantifying, however, the magnitude of each microclimatic parameter is not trivial, especially because affected by dynamic and granular anthropogenic forcing. Instead, due to the complex morphology of urban areas, microclimatic conditions have been found to significantly vary not only among different cities but also among different locations of the very same city33. For instance, UHI incidences has been found not only between urban and rural areas but also between urban and suburban areas35. In general, the profile of each investigated urban microclimate is determined by the unique characteristics of the corresponding area36. Therefore, the intrinsic inhomogeneity of urban microclimate needs to be in-depth investigated with respect to the spatio-temporal variations originated from the local morphology, anthropogenic actions, urban planning, and temporal weather conditions39. For precisely determining the gradient and the intra-urban deviations of microclimatic variables, their spatial extent needs to be thoroughly delineated. Mapping out each variable’s footprint can result in a better understanding and evaluation of cities’ function, as well as decreased biases concerning local phenomena, such as UHI magnitude and its consequent heat stress and risk mapping. Furthermore, more efficient comparison analysis among relevant studies will be feasible40.Measures for counterbalancing UHI and its aftermaths are deemed of critical importance. In fact, techniques for controlling the variables regulating the urban microclimate are receiving increased attention from academics, urban planners and policy-makers41 utilised and retrieved data from a network of 23 experimental weather station within the city of Athens and gauged the corresponding UHI magnitude while the same did Yang et al.16 in the city of Nanjing, China and Foisard et al.42 within the city of Rennes, France by implementing networks of 15 and 22 weather stations, respectively. Similarly, Richard et al.43 employed an extended network of 47 fixed air temperature sensors for identifying thermal zones within the city of Dijon, France during a 3-week heatwave. Another sensor network of high density is established by the Birmingham Urban Climate Laboratory and comprises 29 sensors distributed within the entire city of Birmingham44. Results of such studies are of critical importance since not only gauge the magnitude of local phenomena, such as UHI, but also shed light on the corresponding mechanisms of urban climate and hence help towards efficient countermeasures. However, since in most cases meteorological stations are sparsely distributed, data retrieved from this method represent a point-wise momentum of each microclimatic variable and not the overall footprint and the corresponding spatial patterns16.Traditionally, in-situ meteorological stations have been implemented for measuring parameters such as air temperature and humidity, in and out of the city. For instance, Santamouris et al.46 for assessing UHI and its drivers within high populated cities in China. However, due to their typically low temporal resolution, together with lack of direct air temperature profiles, data retrieved from satellites cannot be used for evaluating an extensive intra-urban distribution of UHI.To overcome this limitation, recent studies employed remote sensing techniques. In fact, land surface temperature (LST) data from satellites have been widely utilised for measuring the magnitude of microclimatic variables determining surface UHI mainly due to their high spatial resolution. For example, several studies used MODIS LST data47 utilised vehicular temperature traverses in order to determine the spatial variability of air temperature at two-meter height across the metropolitan area of Portland, US. Santamouris et al.48 developed a mobile weather station on a telescopic mast placed atop of a vehicular van capable of measuring air temperature, wind speed, and direction at different heights with time-step of 30 s and performed a monitoring campaign before and after the implementation of cool pavements in an urban park at the city of Athens, Greece. Similarly, Busato et al.34 assessed UHI incidences within the city of Padua, Italy through the development and utilisation of a mobile weather station built on a vehicle and capable to measure air temperature, relative humidity, and solar global radiation with a time-step of 5 s. Mobile weather units were employed also in the study of Parece et al.49 aiming to capture spatial patterns of air temperature (2 s time-step) across the Roanoke, Virginia, USA. Santamouris et al.50 also developed a mobile weather station, called “EnergyBus”, that measures air temperature, relative humidity, pressure, and wind speed.Under this framework, mobile meteorological units, placed typically on motorized vehicles, are becoming popular among academics for determining the spatial variability of microclimatic variables within a city. Table 37 and trolleys62 in order to monitor pedestrian pathways and the corresponding thermal comfort. Nevertheless, areas of vehicular traffic dominate typically the outdoor urban environment63. Hence understanding the differing and localized patterns of the parameters that regulate the corresponding microclimate through an exhaustive monitoring techniques is of primary importance. That said, both weather variables, such as temperature, humidity, wind speed and direction, and parameters, such as materials implemented into the built environment, must be taken into consideration. Subsequently, thermal environment and comfort can be efficiently accessed and evaluated for safeguarding the well-being of the citizens.Moreover, mobile weather stations have been also developed on human-wearable helmetUnder this framework, this study aims to contribute towards detailed monitoring techniques that can identify the environmental quality of urban areas and hence safeguard fine standards of the corresponding risk and resilience planning. It presents the application of an advanced mobile weather station within a city of central Italy. The mobile station can monitor profiles of the main parameters that regulate the lower levels of a typical urban canopy layer. More specifically, it can monitor not only scalar or vector variables such as air temperature, humidity, wind profile, and air pollutants’ concentration, but also directionally dependent variables, such as reflected and diffused shortwave radiation and illuminance that are typically affected by the properties of urban surfaces. The start-up of the novel methodology is demonstrated through two transect campaigns during the winter period of 2020 within the historical city of Perugia, Italy. The main variables that define the quality of a typical urban environment were subsequently mapped and evaluated in terms of intra-urban variations within districts of different morphology.The mobile monitoring station includes five units equipped on the 3D surface of the vehicle Fig. . All uniFor that reason, in order to ensure an accurate point-wise microclimatic representation of the investigated route, the mobile station presented here is equipped with five pyranometers each one facing towards a different direction. Similarly, five luxmeters were placed towards different orientations for capturing directional illuminance. In more detail, solar global radiation and illuminance are measured each by five different sensors oriented towards (1) the sky, (2) the street, the (3) right, the (4) left, and the (5) backside of the vehicle. The sensors are positioned on the top and back facades of the vehicle so as to minimize both external interferences, e.g. shading effects, and overlapping incidences. Furthermore, in order to ensure an accurate air temperature profile, a corresponding probe is placed in each of the five units. It should be mentioned that in the present study the air temperature probe of unit no. 5 was not utilized. All measurements are taken at the same timestamp every 10 s.64.The sensor’s main characteristics, such as operation range, accuracy, and sensitivity error are opted for ensuring the desired level of precision of the corresponding variables. All the main technical characteristics of the installed sensors are summarized in Table Once the transect is concluded, data loggers of the designed configuration automatically generate a “.csv” file in which all data are saved. Data retrieved from the GPS antenna are also included in the same file and were utilized for intra-urban illustration. In order to minimize overheating incidences and ensure aspiration by vehicle’s motion to the extent possible, the sensors of temperature were placed and ventilated in a PVC radiation shield. All sensors utilised in this study are commercially available products, thus are tested, validated and certified in terms of accuracy by the producing company following the corresponding protocol and standards.65. Moreover, during the winter period, the city of Perugia is characterized by standard anthropogenic actions, e.g. standard working and school schedules, affecting the thermal environment and air quality, whilst during the summer period, possible biases may occur due to tourism forcing and varied school and working schedules. Previous studies showed that correlations between microclimate parameters and urban morphology are more accurate in terms of statistical significance during clear sky conditions and generally stable boundary conditions37. Hence, one clear sky day-time and one clear sky night-time days were chosen for carrying out the presented monitoring campaigns  and night-time (after sunset and thus in absence of incoming shortwave radiation). The monitoring campaigns were carried out by the authors during the months of January and February of 2020, i.e. in winter conditions. The winter period is a rather under-reported period in terms of mobile microclimate monitoring, while the UHI phenomenon could lead up to +9° in core cities with respect to rural surroundings66. The pathway  a hilly Medieval city center which is densely built, mainly characterized by stones and bricks as prevailing built materials, and not fully accessible by vehicles; (2) modern urban neighborhoods developed in proximity of the main train station and the main infrastructures connecting the historical city to its surroundings, that are similarly characterized by mid-rise buildings but wider roads, a higher amount of pollutants and anthropogenic heat sources, and prevailing asphalt and concrete as built materials; (3) suburbs that are outer from the center, sparsely built, and with a higher amount of greenery. Further details of each area with respect to the monitoring path can be found in Table 56. However, due to vehicular traffic, the day-2 monitoring transect exceeded the one-hour duration by 10 min.Both monitoring campaigns followed the very same pathway within the city of Perugia, in central Italy. According to the Köppen and Geiger classification, Perugia is classified as Cfa and is characterized by humid subtropical climate conditionsway Fig.  is almos36, while according to Taha et al.56 measurements of air temperature at vehicle speed lower than 10 km/h should be discarded. Other mobile monitoring studies, however, reported vehicle speeds above 30 km/h59. Here, in order to maintain the lowest possible speed within the city area and get a substantial spatial resolution, vehicle speed was maintained around 20 km/h and hence measurements were taken approximately every 50 m.Concerning mobile monitoring, a vehicle’s speed of 10 km/h is recommended by Oke68 were retrieved for defining the boundary conditions of each monitoring campaign in terms of air temperature and shortwave radiation. As it can be seen in Fig. At first, data derived from a stable weather station built on the roof of the University of PerugiaA representation of intra-urban variations of some of the collected variables can be seen in Fig. A more precise picture of the variable profiles can be observed through the illustration of the corresponding time-series. In Fig. The temperature substantially dropped  and air temperature and PM10). Likewise, primary relationships within the measured variables were moderate to low during night-time monitoring. A negative primary relationship was observed concerning altitude and air temperature  on day-2. In addition, during the same day, a positive relationship can be seen for altitude and PM10 .During the day-time monitoring campaign, the most significant relationship was positive and found for air temperature and absolute humidity, i.e. r = .69, Multiple linear regression was employed to further investigate the relationship between air temperature, i.e. dependent variable, and the other measured microclimate parameters, i.e. independent explanatory variables. Air temperature is chosen as the dependent variable since is the main parameter that directly demonstrates the thermal environment of a typical urban environment. Moreover, datasets of both day-1 and day-2 meet the main assumptions of linear regression, i.e. multivariate normality, no multicollinearity, and homoscedasticity. The standardized residuals of the regression, i.e. the errors between observed and predicted values, are normally distributed Fig. a,b. Therp-value of model’s F-statistic is < 2.2e−16, which is statistically significant, i.e. at least one explanatory variable is significantly related to the air temperature. Concerning day-1, a significant relationship with p < .001 is found between air temperature and each of absolute humidity, PM10, p = .003 is found between air temperature and altitude (h). Concerning day-2, a significant relationship with p < .001 is found between air temperature and each of absolute humidity, PM10, p = .001 is found between air temperature and wind speed (WS). The values of the adjusted R-squared suggest that the models explain a 68% and 58% of the variance of air temperature, concerning day-1 and day-2, respectively.Concerning both day-1 and day-2, the The current study reports on the application of advanced mobile monitoring techniques within a historical lively city of central Italy. Locating hot-spots with respect to each microclimate parameter, as well as identifying possible relationships among them is not trivial. Each city is characterized by its specific peculiarities. Perugia, the city chosen for the present study, is characterized by a diverse morphology. It comprises a city center with narrow and shaded streets with limited vehicular traffic, a more recent neighborhood developed around the main train station with substantial anthropogenic action, and several mostly residential suburban areas with open-air streets, and greenery. Here, a novel mobile monitoring station is implemented for monitoring the main micro-meteorological variables that affect climate and environment with high spatial granularity for both microscale, i.e. neighborhood-scale, and mesoscale, i.e. city-scale. The developed station can be easily adjusted to different type of vehicles such public transportation, electric cars or other dedicated monitoring vehicles. The main stimulus of its development was to gauge and map intra-urban deviations of the main variables determining urban microclimate, also imputable to anthropogenic actions. In this view, the scale of the analysis here reported is the neighborhood scale. Nevertheless, the system’s potentiality in retrieving analysis at higher-granularity is pointed out as well. Following an observational mobile-transect methodology, the station can access and monitor almost all areas accessible by car. Unlike mobile monitoring techniques implemented to date on a macro-scale within urban areas, the presented technique succeeds the detailed monitoring of scalar, vector, and directionally dependent variables. A start-up assessment was carried out in winter conditions, a period under-reported in particular in terms of mobile monitoring, and UHI studies. Results showed that determinants of urban microclimate and hence the quality of the urban environment can substantially vary within the very same urban context and with time Table . Moreove