Cynanthus latirostris, 3.0 g), black-chinned , Rivoli's  and blue-throated  hummingbirds in southeastern Arizona and calliope hummingbirds  in Montana. Thermal gradients driving passive heat dissipation through eye, shoulder and feet dissipation areas are eliminated between 36 and 40°C. Thermal gradients persisted at higher temperatures in smaller species, possibly allowing them to inhabit warmer sites. All species experienced extended daytime periods lacking thermal gradients. Broad-billed hummingbirds lacking thermal gradients regulated the mean total-body surface temperature at approximately 38°C, suggesting behavioural thermoregulation. Blue-throated hummingbirds were inactive when lacking passive heat dissipation and hence might have the lowest temperature tolerance of the four species. Use of thermal refugia permitted hummingbirds to tolerate higher temperatures, but climate change could eliminate refugia, forcing distributional shifts in hummingbird populations.At high temperature (greater than 40°C) endotherms experience reduced passive heat dissipation  and increased reliance on evaporative heat loss. High temperatures challenge flying birds due to heat produced by wing muscles. Hummingbirds depend on flight for foraging, yet inhabit hot regions. We used infrared thermography to explore how lower passive heat dissipation during flight impacts body-heat management in broad-billed ( Low mechanical efficiency of flight muscles results in substantial heat generation during flight in birds ,2 that m12 m s−1 . At highWhen environmental temperature becomes sufficiently high to eliminate passive heat dissipation, the only avenue for heat loss in flying birds is evaporative water loss (EWL). The ability to use EWL to compensate for the loss of passive heat dissipation will probably vary among bird species based on their physiological and ecological characteristics –9. In reBirds must cope with a range of daily and annual temperatures. In warm environments, some hummingbirds avoid high temperatures by reducing their activity during the middle of the day . In thermally complex habitats, birds can adjust behaviour to take advantage of cooler refugia to slow the impact of increasing environmental temperature . However−1 [−1 [Hummingbirds are an excellent model for the study of heat dissipation during flight because they can live in hot climates ,21, and −1 , whereas−1 [−1 ,24. At h−1 [−1 . Thus, c−1 [−1 . If therIn this study, we use measurements of operative temperature  and infr2.2.1.Platanus wrightii) surrounded by oak–mesquite  at higher elevations. Sonoita Creek State Natural Area , elevation 1150–1250 m, was characterized by riparian vegetation along Sonoita Creek that included large sycamores, cottonwood, ash and willow surrounded by high desert vegetation including mesquite, acacia, ocotillo, yucca and various cactus species. HC is climatically influenced by the Sonoran Desert, while SC is a transition zone between the Sonoran and Chihuahuan Deserts. At both sites the environmental temperature approaches 50°C during summer.Field measurements were conducted at four sites in southeastern Arizona May–August 2013 and 2014. Two study sites were near the town of Patagonia, Santa Cruz County. Harshaw Creek , with an elevation range of 1375–1635 m, had riparian vegetation along HC that included large sycamores  is on the western slope of the Chiricahua Mountains and at an elevation range of 1700–2050 m. The site consisted of a variety of habitats that included various mixtures of pine, juniper, oak, a few other broad-leaf species and a small amount of grassland. The Southwestern Research Station  is on the eastern slope of the Chiricahua Mountains at an elevation range of 1640–1900 m. The site included sycamores, alder and willows in the riparian zones surrounded by pine–oak or pine–juniper forest .Tbody) and the mean HDA surface temperature (THDA) on captive birds were made at HC and SWRS in southeastern Arizona and at the University of Montana Flight Lab, Missoula, Montana . Temperature-related symbols used in this study are defined in IR thermography measurements of the mean surface temperature  and black-chinned hummingbird  June–July 2013. At both EC and SWRS, we studied Rivoli's hummingbirds  and BCHU, and at SWRS blue-throated hummingbirds . Laboratory studies on captive birds were done at SWRS during June 2013, and studies of free-living birds done at both EC and SWRS during June–July 2014. All Arizona species arrive on site from Mexico in spring and are present through most of summer [Selasphorus calliope; three males, 2.4–2.9 g; four females, 2.6–3.1 g; CAHU) were studied in the laboratory during June 2010–2012 in Missoula, MT (Missoula County), USA.At HC and SC, we studied captive and free-living broad-billed hummingbird  and the University of Montana IACUC (002–12BTDBS-012012). Collection of hummingbirds for our laboratory and field studies was authorized by the US Fish and Wildlife Service , Arizona Department of Game and Fish  and Montana Fish, Wildlife, and Parks (permit no. 2012-34).2.3.Te) using Cu–Cn thermocouples (type-T) inside hollow copper spheres (0.53 cm3) painted flat grey [Te at 15 min intervals. For analysis of IR thermography data (see below) we used the site-specific mean Te recorded closest to the time data were collected (within ± 7.5 min).We measured operative temperature .To measure surface temperature of hovering hummingbirds, we recorded IR images using a FLIR SC6700 IR video camera . Recordings were made of both free-living hummingbirds at a feeder and captive birds housed in a 1 mingbirds . For eacTbody,°C), HDA surface temperature  and ambient temperature ; Ta was measured by recording an IR image of a black cloth that lined the rear wall of the chamber. This method of measuring Ta was validated with concurrent measurements of internal chamber Ta using a type-T (Cu–Cn) thermocouple; Tbody was measured by tracing the outline of the lateral body view in each IR image; and THDA was an integrated measure of the traced eye, axial and feet/legs HDAs  and length along a transect from the base of the bill, through the eye, to the back of the head. We used a transect because at high temperature the boundary of the eye HDA becomes obscured. Boundaries for the eye HDA were assumed to be where the surface temperature along the transect increased above Tbody (excluding the eye). For each of the temperature measurements described above, mean, minimum and maximum values were recorded.For captive birds, each single-frame image was analysed for whole-body (plumage) surface temperature  was estimated as ΔT = THDA − Te in captive birds, and ΔT = Teye − Te in free-living birds. The ΔT values calculated when Teye < Te are shown graphically, but not included in regression models because Teye cannot be accurately measured under these conditions.The thermal gradient for passive heat transfer . The hu [et al.  was used3.Te at both Patagonia and the Chiricahuas differed by greater than 20°C, with maximums at SC in Patagonia occasionally near 50°C. In Patagonia, at HC the mean hourly temperature was cooler and more variable than SC. In the Chiricahuas, the mean hourly temperature was cooler at SWRS than EC except during 11.00–12.00. Hourly temperature was also more variable at SWRS . Over the same Ta range the integrated mean THDA showed no relationship with Ta (pMCMC < 0.08). Assuming a mean model intercept for all species included in the analysis, the size of the thermal gradient (ΔT) was negatively correlated with Ta (R2 = 0.971), and ranged from 12.7°C at Ta = 18.4°C to 4.4°C at Ta = 28.4°C (ΔT = 30.21–0.92Ta).Bayesian MCMCglmm, including phylogeny to estimate statistical significance, showed that laboratory measurements of Te and both Tbody and Teye are consistent with laboratory observations. Typical lateral IR images and corresponding three-dimensional surface plots for BBLH are shown in T confirm that ΔT was negatively correlated with Te, and that when Te approaches 40°C, there was no longer a sufficient ΔT to support passive heat dissipation.IR images of free-living hummingbirds show that the relationships between T and Te among species (T = 0 (ΔT0) when Te is 40.4°C and 39.6°C, respectively  into the eye HDA proper .Eye HDA length and Δ species , but in T and eye HDA length . The length of the eye HDA was variable probably due to the rapid rate of decrease in eye HDA length when ΔT is small . Although we had relatively few measurements of BLUH (n = 17), it was interesting that data were absent from 12.00 to 18.00, which includes periods of the day when ΔT was unfavourable. Unlike BLUH, RIHU were more active midday (12.00–15.00) even though Te was near ΔT0 (d).There was variation in daytime ΔA length . For BBL than HC a. The leis small . Variabl the day b. Althounear ΔT0 d.FigureTbody increased with Te until Te was near ΔT0 , suggesting that Tbody was intentionally regulated. Regulation of Tbody above ΔT0 might also be occurring for BCHU and RIHU, but the number of high Te measurements (Te > ΔT0) for these species was limited . No measurements of BLUH beyond ΔT0 were made, so their response to high Te remains unknown.For free-living birds near ΔT0 . In BBLH4.Teye and behavioural data suggest that hummingbirds in this study must rely primarily on evaporative heat dissipation for body-temperature management when Teye approaches Te , suggesting that heat dissipation during flight would require dependence on evaporative heat dissipation for extended periods during the day  in southeastern Arizona lose their ability to passively dissipate heat, they appear to actively regulate their Tbody during hovering to avoid passive heat gain and protect themselves from hyperthermia . When Te exceeds ΔT0, heat balance becomes challenging because of passive heat gain due to reversal of the thermal gradient, and the need to rely solely on evaporative heat dissipation for cooling. REWL accounts for 30–35% of total heat dissipation in all our study species at Te ∼ 40°C [While is study . Thus, ae ∼ 40°C , requirie ∼ 40°C , so CEWLTe does occur in birds. At extremely high Te (greater than 50°C) resting arid-zone columbids dramatically increase CEWL, allowing them to maintain body temperatures below their thermal endpoints [Te in smaller resting passerines is dominated by REWL (panting) [Substantial upregulation of CEWL at high ndpoints . Howeverpanting) ,38. Anecpanting) –41), mucpanting) , making Te, with the smaller species appearing to be more tolerant of high Te than the larger species. Both BBLH and BCHU exhibited higher ΔT0, and slower decrease in ΔT and eye HDA length as Te increased compared to BLUH and RIHU  or Lucifer's hummingbird ), so the relationship between body size and thermal tolerance merits broader comparative study.Hummingbird species in this study showed differences in their response to high and RIHU . Higher he wings . Our resTHDA approached ΔT0 . In the Chiricahua sites, Te was cooler, but still could exceed BLUH and RIHU ΔT0 for several hours. RIHU were transient at our sites, so it was difficult to determine how long individuals remained at our feeders. Individual RIHU tended to perch in nearby trees, making foraging bouts short, which could reduce total heat production during flight, thereby allowing intermittent foraging even at higher Te. No BLUH measurements were recorded in this study between 12.00 and 17.30 at SWRS, suggesting a substantial reduction of flight activity during the warmest times of day. Interestingly, Te values during this period of BLUH inactivity roughly corresponds to the range of Te values over which most of our BCHU measurements occurred. It is possible that the BCHU ability to maintain a favourable ΔT over the range of Te we measured allowed them to forage frequently during midday with minimal disturbance from BLUH, and could be an example of temporal/thermal niche partitioning. Temporal partitioning has been suggested as a way for a wide range of species who use the same resource to coexist [ept BCHU . Sonoita coexist –50. Ther coexist . While o coexist .Tbody suggest behavioural shifts at high Te  how hovering hummingbirds manage body heat at high temperature and (ii) the upper limits of temperature tolerance will require measurements of evaporative heat dissipation during hovering, and specifically measurements of CEWL.Populations of hummingbird species in this study are common and the primary breeding species at our study sites, yet they are seemingly obligated to make physiological and/or behaviour adjustments at high temperature as a thermoregulatory strategy to mitigate the effects of high body-heat load. The two smaller species in this study appear to tolerate higher temperatures better than the larger species as indicated by their higher Δ


Evidence shows altered somatosensory temporal discrimination threshold (STDT) in Parkinson’s disease in comparison to normal subjects. In healthy subjects, movement execution modulates STDT values through mechanisms of sensory gating. We investigated whether STDT modulation during movement execution in patients with Parkinson’s disease differs from that in healthy subjects. In 24 patients with Parkinson’s disease and 20 healthy subjects, we tested STDT at baseline and during index finger abductions . We also recorded kinematic features of index finger abductions. Fifteen out of the 24 patients were also tested ON medication. In healthy subjects, STDT increased significantly at 0, 100, and 200 ms after movement onset, whereas in patients with Parkinson’s disease in OFF therapy, it increased significantly at 0 and 100 ms but returned to baseline values at 200 ms. When patients were tested ON therapy, STDT during index finger abductions increased significantly, with a time course similar to that of healthy subjects. Differently from healthy subjects, in patients with Parkinson’s disease, the mean velocity of the finger abductions decreased according to the time lapse between movement onset and the delivery of the paired electrical stimuli for testing somatosensory temporal discrimination. In conclusion, patients with Parkinson’s disease show abnormalities in the temporal coupling between tactile information and motor outflow. Our study provides first evidence that altered temporal processing of sensory information play a role in the pathophysiology of motor symptoms in Parkinson’s disease. Sensorimotor integration is the process whereby incoming sensory information is continuously monitored so as to allow the current motor plan to be adjusted and voluntary movements to be executed accurately –5. SensoSeveral studies have consistently reported abnormally high STDT values in patients with Parkinson’s disease , 11–15. The aim of this study was to investigate whether STDT modulation during movement execution in PD patients differs from that in healthy subjects and to evaluate changes in the kinematic properties of movements during the sensorimotor integration task. We also investigated the effects of dopaminergic therapy on movement-induced STDT modulation. Finally, we investigated possible correlations between neurophysiological and clinical variables.We enrolled 24 patients with Parkinson’s disease  and 20 age-matched healthy subjects  at the Department of Neurology and Psychiatry of the University of Rome, Sapienza. All the participants gave their written informed consent. The experimental procedure was approved by the institutional review board at Sapienza University Rome and conducted in accordance with the Declaration of Helsinki. The diagnosis of PD was based on clinical criteria , 18. DisAll the PD patients were studied OFF therapy . Fifteen of the 24 PD patients were also tested in “ON” state after receiving levodopa; the two sessions in these patients were performed in a randomized order, at least 1 week apart.STDT was investigated on the volar surface of the index finger of the right hand and of the left hand in patients and of the right hand in healthy subjects, according to the experimental procedures previously used , 19, 20.EMG activity was recorded through surface electrodes placed over the FDI muscle, in a belly tendon configuration. EMG signals were recorded and filtered with a Digitimer D360  (bandwidth 20 Hz–1 kHz), then analyzed off-line with a personal computer through a 1401 plus A/D laboratory interface . Data were stored on a laboratory computer for on-line visual display and further off-line analysis .via a dedicated software that runs the automatic algorithm to compute the range of motion (ROM), which represents the displacement of the index finger around its metacarpophalangeal joint expressed as the degree of the angle and mean velocity (degrees per second) .The SMART analyzer motion system , equipped with three infrared cameras , was used to record index finger abductions. The arm was abducted at the shoulder by about 45–50°, and the elbow joint was flexed at about 90°. An optical marker was placed over the distal phalanx of the index finger. After a verbal “go” signal, subjects abducted the index finger, then returned the finger to the starting position upon being given a verbal “stop” signal shortly after –23. MarkExperimental procedures envisaged first the assessment of basal STDT values (without movement). Participants were then instructed to perform index finger movements. Subjects were asked to abduct the index finger as widely and as quickly as possible and were continuously encouraged to do so throughout the motor task. Participants performed 10 index finger abductions before starting the experiment to familiarize with the motor task required . The experimental tasks consisted of index finger abductions, with the STDT being tested on the volar surface of the same index finger. Paired stimuli for STDT were triggered by movement execution at various time lapses after movement onset. The threshold to identify movement onset of index finger abductions was set at 100 μV of EMG activity. To define the time course of movement-induced STDT changes, paired stimuli were delivered as soon as the EMG signals reached 100 μV in amplitude (defined as “0 ms” for simplicity), 100 and 200 ms after movement onset. The STDT values were thus calculated for each time lapse . At each index finger abduction, the ISI for STDT testing was progressively increased in 10-ms steps, until the subject recognized the two stimuli as sequential  and neurophysiological results. P < 0.05 indicated statistical significance.We first checked STDT and kinematic data for normal distribution using Shapiro–Wilk test. Having excluded any assumption violations, we then performed separate between-group ANOVA to compare baseline absolute values of STDT and kinematic values (ROM and mean velocity) in healthy subjects and patients with Parkinson’s disease. To evaluate any difference in the amount of STDT modulation and changes in kinematic variables during movement execution between patients and healthy subjects, we used separate between-group repeated measure ANOVA with factor GROUP and factor TIME LAPSE  entering percentage values. To evaluate changes in the STDT modulation and kinematic variables induced by dopaminergic therapy, we used separate repeated measure ANOVA with factor THERAPY (two levels: ON and OFF), SIDE (more and less affected hand), and TIME LAPSE . As a T test: P = 0.43) and sex (Mann–Whitney U test: P = 0.77).PD patients and healthy subjects did not differ in terms of age  = 26.4, P < 0.0001; less affected hand: F = 32.0, P < 0.001] as well as ON therapy  were higher than in healthy subjects. No significant difference was observed in the baseline STDT values of PD patients between the more affected and less affected hand   = 7.8, P = 0.008; less affected hand OFF therapy: F = 4.5, P = 0.03], factor TIME LAPSE , and a significant GROUP × TIME LAPSE interaction . Between-group ANOVA to compare changes in STDT values during index finger abductions in patients ON therapy and healthy subjects showed a significant factor TIME LAPSE  but not significant GROUP × TIME LAPSE interaction. Post hoc analysis showed that the increase in STDT values in healthy subjects was significant at 0 ms (P < 0.0001), 100 ms (P = 0.001), and 200 ms (P = 0.002). In PD patients in the OFF therapy condition, the STDT increased at 0 ms  and 100 ms  but returned to baseline values at 200 ms . In PD patients ON therapy, the STDT increased significantly at 0 ms , 100 ms , and 200 ms   = 9.8, P = 0.007], factor TIME LAPSE  and a significant THERAPY × TIME LAPSE interaction . STDT values in PD patients were significantly higher OFF therapy than ON therapy  = 7.7, P = 0.008; less affected hand OFF therapy: F = 14.0, P = 0.0001; more affected hand ON therapy: F = 14.3; P < 0.001; less affected hand ON therapy: F = 6.8, P = 0.01; mean velocity: more affected hand OFF therapy: F = 27.2, P < 0.001; less affected hand OFF therapy: F = 24.9, P < 0.0001; more affected hand ON therapy: F = 15.2, P = 0.001; less affected hand ON therapy: F = 14.4, P = 0.001]  = 4.7, P = 0.03], but no significant factor TIME LAPSE  or TIME LAPSE × GROUP interaction .Between-group repeated measure ANOVA to compare percentage changes in ROM during index finger abductions in PD patients and in healthy subjects across the various time lapses tested showed a significant factor GROUP , factor TIME LAPSE , and a significant GROUP × TIME LAPSE interaction . Index finger abductions were slower in both hands in PD patients OFF therapy than either in those ON therapy or in healthy subjects at all the time lapses tested . Post hoc analysis performed to evaluate percentage changes in the mean velocity of index finger abductions during STDT testing showed that the mean velocity in PD patients, unlike that in healthy subjects (in whom the mean velocity was not affected by STDT testing) (P > 0.05), significantly decreased across time lapses, with lower values being recorded at 200 ms  than at 0 ms interval  = 7.4, P = 0.001]. When PD patients were tested in OFF therapy condition ROM slightly decreased across ISIs, being smaller at 200 ms interval in comparison to 0 ms interval, whereas, when PD patients were tested in the ON therapy condition, similar to healthy subjects, ROM remained unchanged across time lapses.ANOVA performed to analyze changes in ROM induced by dopaminergic therapy in PD patients revealed a significant HAND × THERAPY × TIME LAPSE interaction , and a significant TIME LAPSE × HAND × THERAPY interaction . In PD patients, dopaminergic therapy increased the mean velocity in both the less affected and the more affected hand. The increase in mean velocity induced by dopaminergic medication was more evident at the 0 ms than at 200 ms interval, as well as in the less affected hand than in the more affected hand   .Changes in mean velocity in the more affected hand OFF therapy at 200 ms interval were inversely related to the UPDRS part III score OFF therapy  Figure . We did The results of this study first confirm that STDT values are higher in PD patients than in healthy subjects –16, 19. Since we randomized the order of the trials testing the different time lapses between movement onset and paired stimuli for STDT, we are confident that changes in the STDT values and in movement kinematics did not depend on different attention levels or fatigue. Similarly, we alternated the order of the OFF and ON medication conditions. Thus, since the time lapses and medication conditions were randomized, the changes we observed in movement kinematics at different time lapses suggest that they were due specifically to the time lapse between movement onset and paired electrical stimuli. We also rule out that the time course of the STDT changes during index finger abductions in the OFF therapy condition was due to the higher baseline STDT values in PD patients because the STDT increased significantly at 0 and 100 ms. Moreover, with the stepwise method, we used for STDT, a floor effect might occur in experimental protocols in which STDT values are expected to decrease below the threshold, whereas values may increase to a considerable extent above the threshold.l-DOPA likely improves the time-related interaction between corticosubcortical structures (The distinctive finding of our study is that temporal coupling of tactile sensory information processing and motor outflow is altered in PD patients, which extends our knowledge by bridging the gap between altered temporal processing of sensory information and motor symptoms. We show that sensory information processing related to STDT is abnormally gated during movement execution in PD patients OFF therapy if compared with healthy subjects and those ON therapy. Using our time-controlled experimental paradigm, we now provide evidence that tactile information gating is less efficient in PD patients than in healthy subjects, as indicated by the observation that STDT values of PD patients OFF therapy returned to those at baseline when STDT was tested 200 ms after movement onset, whereas the STDT was still gated in healthy subjects at this time interval. We therefore hypothesize that dopaminergic depletion in PD not only affects sensory processing in the temporal domain but also alters the temporal coupling between tactile information and motor outflow. Consistent with previous observations , 19, 24 ructures , 19 but ructures , 24–27. In keeping with previous studies –30, indeIn conclusion, altered tactile–motor integration, in addition to the previously reported proprioceptive–motor integration , 40–44, All the participants gave their written informed consent. The experimental procedure was approved by the institutional review board at Sapienza University Rome and conducted in accordance with the Declaration of Helsinki.AC and DB: conception/design/execution of the project/drafting the manuscript. MT, NC, VB, EB, and XZ: acquisition of data/data analysis. GF and AB: revising the work critically for important intellectual content. All authors: manuscript preparation.AC received funds from Sapienza University of Rome for a research project on movement disorders. DB, MT, NC, VB, EB, and XZ reported no disclosure. GF received funds from Sapienza University of Rome for research projects on movement disorders. AB received funds from the Benign Essential Blepharospasm Research Foundation for research on blepharospasm. He has received national grants from Italian Ministry of University and Sapienza University of Rome, Chiesi, Lundbeck, Merz, Allergan, Ipsen. He has received honoraria for lecturing from Boehringer Ingelheim, GSK Pharmaceutical, Novartis Pharmaceuticals, Lundbeck, Chiesi.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.


Gc number as a criterion to judge air stability. Furthermore, we find the phenomenon of inertia conjugation. Air stability and inertia conjugation, which named together as temperature background effect, work together on interactive respiration process. This work gives us a re-orientation of temperature difference agents and thus improves human being’s living environment.Indoor air quality (IAQ) is much more crucial to human health than its atmospheric air quality counterpart. Improving indoor air environment requires investigating how different indoor air stability affects airflow trajectory. By presenting both manikin experiment and Computational Fluid Dynamics (CFD) simulation, we find that temperature background effect, i.e., indoor air stability, which is a measure of the nature or attribute of the capacity to keep the original or initial inertia force or inertia transmission state instead of turbulence diffusion or transmission restraining state, i.e., a kind of inertia stability, rather than a turbulence diffusion characteristic stability, is markedly affecting the interactive respiration process. So we define and derive a new parameter called  However, in limited spaces, such as indoor environment, the same air stability problem still exists, which has a more serious impact on human health, for human beings spend most of their lifetime in interior spaces. Several studies have been made to identify the distribution of pollutants carried in patients’ expiratory airflow in different indoor environment22, and the effect of different indoor ventilation patterns on the transport characteristics of airborne expiratory droplets has also been studied25. In general terms, the phenomena of interactive respiration process characteristics under the temperature difference condition are interpreted as diffusion effects so far. Especially, Richardson Number (Ri) has been adopted to analyze the relationship between the temperature difference and turbulence diffusion term in atmosphere stability. Nowadays, air stability analysis includes static air stability and Ri analysis that can help us understand the turbulence diffusion character, however, they can not explain the dispersing pattern in main-flow direction, i.e., actually a kind of conjugation phenomena. So, Gc number is put forward in this study as a criterion to judge air stability and we need to rethink the nature of the air stability through interactive respiration process analysis here. We provide a genealogy of the temperature difference or small density difference effects  term of Bousinesq’s approximation to the convective inertia force (migrating inertia force) or acceleration term. Gc number is set up by a dimensional analysis and order of magnitude analysis of differential equation based on principles of extended Reynolds Analogy and molecular transport, and is more suitable to reflect the impacts of inertia stability than Ri number in Navier-Stokes or Euler Equations. Here we employ a simplified form of Gc, i.e., Gc is the number of the temperature or density difference source to convection or advection term along vertical or gravity direction. In order to make judgment criterion more clear, we also employ Gc, which is:Ar is the Archimedes number, Fr is the Froude number. When Tt < Tb, indoor air is in an unstable pattern, Gc = −119.94 < 0, Tt ≈ Tb, indoor air is in a neutral pattern, Gc = ∞, Tt > Tb, indoor air is in a stable pattern, Gc = 119.94 > 0, Gc number mentioned above, we prefer to rethink turbulence is a kind of continuing and compact inertia broken and lost. And the conjugation phenomenon is also a kind of inertia conjugation of transmission process as shown in Fig. Temperature difference affects atmospheric stability, which attributes to haze accumulation in human habitants. There are some literaturesGc = −119.94 < 0, Gc = 119.94 > 0, Gc = ∞, In order to investigate more details of the interactive respiratory process, we conduct both model experiment and numerical simulation. When exhaling velocity is 3.9 m/s, in exhaling process, the mainstream concentration in unstable case (ase Fig. 3, inertiase Fig. 1, pollutase Fig. 3, the smase Fig. 1, pollutGc = −119.94 < 0, Gc = 119.94 > 0, Gc = ∞, When inhaling velocity is 3.9 m/s, in inhaling process, the mainstream intensity in unstable case (ity Fig. 3. From tWhen inhaling velocity is 1.7 m/s, in inhaling process, the characteristics of air stabilities of smoke transmission are the same with that under condition of 3.9 m/s inhaling velocity; but more smoke accumulates together in front of manikin face under the inhaling velocity is 1.7 m/s Fig. . It showTherefore, we can conclude that air stability or inertia stability plays a decisive role on indoor pollutants dispersion. Two facts are found in Fig. 2.Indoor air stability is classified into three different types: unstable, neutral and stable type. Four CFD cases are conducted in this study to represent different indoor air stability types, with one case as a control experiment whose g = 0 m/sGc = −119.94 < 0, Gc = 119.94 > 0, c number is 0 (Fig. We can find in Fig. ase Fig. 1,b2,b3, s 0 Fig. 4,b4,c4, When t = 10 s, the peak concentration in stable case is higher than that in unstable case Fig. , which iThus, we find a kind of inertia conjugation effect that along the mainstream direction, the inertia transmission is strong, while in the other direction the inertia transmission process is weak. When the convective inertia transmission touches obstacle or human body, the inertia accumulation is more obvious because of rebounding and stagnating when air stability or inertia stability is stronger. When gravity does not exist, the simulation results of three conditions are the same. It means if there is no gravity, there is no inertia transmission process variation. Therefore, this study re-structures air stability process as inertia stability process, it shows that temperature background condition affects the interactive respiration process. And this work lays a theoretical foundation to healthy environment control, and may purify human beings behavior in public situation.There are three ways employed for temperature background effect via interactive respiration process. They are semi-analytical method, experiment analysis and CFD simulation, respectively. Amongst them, the experiment analysis used a size of 2.4 m × 1.8 m × 2.6 m room for performing air stability and a same size room is employed in CFD simulation.


IVLBCL) is an aggressive non‐Hodgkin's lymphoma which can present with B symptoms, rash, and neurological deterioration. Up to 10% of cases of IVLBCL are associated with other hematological neoplasms, including this extremely rare presentation of IVLBCL as Richter's transformation in chronic lymphocytic leukemia.Intravascular large B‐cell lymphoma ( Intravascular large B‐cell lymphoma (IVLBCL) is a rare type of non‐Hodgkin's lymphoma associated with intravascular proliferation of malignant cells and diverse clinical manifestations. We report the case of a 76‐year‐old man with a 6 year history of chronic lymphocytic leukemia (CLL), Rai stage 0, who presented with B symptoms, functional decline, and neurological deterioration. Investigations revealed new splenomegaly, cytopenias, elevated LDH, and pachymeningeal thickening on cerebral MRI. There was evidence of CLL on flow cytometry of peripheral blood and bone marrow. Meningeal biopsy ultimately revealed the diagnosis of IVLBCL, which was confirmed to be clonally related to the underlying CLL by polymerase chain reaction (PCR) of the immunoglobulin heavy chain (IgVH) gene. This is an extremely rare case of IVLBCL arising as Richter's transformation in CLL. We review the literature on IVLBCL, with focus on the neurological manifestations of this disease, its coexistence with other hematological neoplasms, and the need for further research to guide treatment of IVLBCL with cerebral involvement.A 76‐year‐old man with a 6 year history of untreated chronic lymphocytic leukemia (CLL), Rai stage 0, was referred to our Hematology service with a 2 week history of fevers, night sweats, productive cough, and marked functional decline. During his admission to hospital, he developed progressive neurological deterioration with confusion, generalized weakness, expressive aphasia, and brief tonic–clonic seizures.On physical examination, the patient was hemodynamically stable but developed periodic fevers >39°C and mild hypoxemia requiring supplemental oxygen via nasal cannula. There was no palpable peripheral lymphadenopathy, although there was dullness to percussion over Traube's space. A violaceous, nonindurated 5 by 6 cm patch was observed on the posterior neck. As the patient's neurological status declined, he was noted to have expressive language deficits. The remainder of the physical examination was unremarkable.The patient's past medical history also included amaurosis fugax, mild Alzheimer's type dementia, remote traumatic brain injury and subarachnoid hemorrhage, and benign prostatic hyperplasia. His current medications included acetylsalicylic acid, tamsulosin, donepezil, and risperidone. Baseline Eastern Cooperative Oncology Group (ECOG) performance status was 0.3. White blood cell (WBC) count was 6400/mm3 with an absolute lymphocyte count (ALC) of 3500/mm3, decreased from baseline ALC of 10,000/mm3 4 months prior to presentation. Smudge cells and small mature lymphocytes were identified on blood smear review. LDH was strikingly elevated at 1322 U/L, and inflammatory markers were raised with CRP 78 mg/L and ESR 25 mm/h. Other markers of cell turnover including uric acid, potassium, phosphorus, and calcium were normal. Serum albumin was 27 g/L without significant proteinuria. Serum creatinine, thyroid‐stimulating hormone, and liver enzymes were within the normal ranges. There was no evidence of hemolysis or disseminated intravascular coagulation with normal reticulocyte count, haptoglobin, bilirubin, prothrombin time (PT), partial thromboplastin time (PTT), and fibrinogen levels. There was no monoclonal protein on serum protein electrophoresis, and quantitative immunoglobulin testing revealed moderate reductions in levels of IgA (0.67 g/L), IgG (4.15 g/L), and IgM (0.33 g/L). An infectious work‐up including cultures of blood, urine, and cerebrospinal fluid (CSF) as well as serologies for human immunodeficiency virus (HIV), hepatitis B virus, hepatitis C virus, West Nile virus, syphilis, and cryptococcus were all negative.Laboratory investigations revealed new cytopenias including a normocytic anemia with hemoglobin (Hb) 117 g/L and thrombocytopenia with platelet count 78,000/mmPeripheral blood flow cytometry was in keeping with the patient's known CLL, with a population of lymphoid cells expressing B‐cell markers CD19, dim CD20, dim CD22, CD23, and dim Cd11c with aberrant CD5 coexpression and dim kappa light chain restriction. Identical findings were obtained on flow cytometry of a bone marrow aspirate and biopsy, with no evidence of marrow involvement by hemophagocytosis or transformed lymphoma.3 and 4 WBCs/mm3; cytology slides revealed no cellular elements. Repeat large volume CSF sampling again demonstrated normal glucose and protein levels with 108 RBCs/mm3 and 3 WBCs/mm3. CSF cytology was significant for the presence of rare abnormal large lymphoid cells, but there were insufficient cells to perform flow cytometry.Computed tomography (CT) scans of the head, chest, abdomen, and pelvis did not identify any lymphadenopathy, but did reveal new splenomegaly measuring up to 16 cm containing several foci of low attenuation. There were also bilateral ground‐glass opacities and interlobular septal thickening within the mid and lower lung zones, as well as small pleural effusions, diffuse body wall edema, and moderate amounts of pelvic free fluid. Echocardiogram revealed normal cardiac function and no pericardial effusion. Magnetic resonance imaging (MRI) of the brain and spine was notable for generalized smooth pachymeningeal thickening and enhancement along the bilateral cerebral surfaces, suggestive of an infectious or lymphomatous process  and LDH (158 U/L), and near complete resolution of the splenomegaly and meningeal thickening on follow‐up imaging. Although he does have ongoing cognitive impairment, his functional status and aphasia have significantly improved with treatment.An empiric trial of oral dexamethasone resulted in resolution of the neck rash and improvement in platelet count and mental status. The patient was treated with six cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP) with CNS‐directed therapy with high‐dose intravenous and intrathecal methotrexate. Seven months after his initial presentation, the patient has completed treatment with improvement of his peripheral cell counts , anemia (63%), elevated ESR (43%), thrombocytopenia (29%), leukopenia (24%), hypoalbuminemia (18%), and a monoclonal serum protein (14%) Intravascular large B‐cell lymphoma (IVLBCL) is a rare and aggressive extranodal non‐Hodgkin's lymphoma characterized by proliferation of neoplastic cells within the lumen of small‐ to medium‐sized blood vessels uminemia 8%, and auminemia 8%, and auminemia 8%, and atopenia 2%, leukopThe predominantly neurological symptomatology of the present case reflects the predilection for CNS involvement in intravascular lymphoma, which occurs in over 40% of affected patients This presentation of intravascular lymphoma arising as Richter's syndrome in the setting of previously stable CLL is extremely rare. To the best of our knowledge, there is only one previous report of IVLBCL associated with CLL Previous studies demonstrate that 80% of cases of IVLBCL arise from a nongerminal center (non‐GCB) cell of origin, as confirmed by immunophenotyping and IgVH variable region gene analyses P ≤ 0.0001) P = 0.15) Treatment of IVLBCL remains difficult and associated with poor outcomes, with a median survival of 5 months from time of symptom onset Intravascular large B‐cell lymphoma (IVLBCL) is a rare and aggressive non‐Hodgkin's lymphoma characterized by the intravascular proliferation of malignant lymphocytes. Clinical manifestations include B symptoms, functional decline, rash, and CNS involvement in over 40% of cases. Diagnosis often requires a high index of suspicion and invasive tissue sampling. Up to 10% of cases of IVLBCL arise clonally or independently from other hematological malignancies, although this presentation of IVLBCL as Richter's transformation in CLL is extremely rare. Standard treatment for IVLBCL consists of R‐CHOP, and the role for CNS‐directed therapy with methotrexate in patients with cerebral involvement requires further investigation.RP: performed the literature review and wrote the manuscript. PP: wrote the manuscript. ZG, JK, LC, and YL: reviewed and edited the manuscript for important intellectual content. JC: supervised the research process and reviewed and edited the manuscript for important intellectual content.Informed consent was obtained from the patient prior to publication of this case report. This case report received no funding from any source.The authors have no conflict of interests to declare.


The association between body mass index (BMI) and clinical outcomes of gastric cancer were still under debate. The aim of the present study was to investigate the impact of BMI on intraoperative conditions, postoperative complications and prognosis of gastric cancer.2), normal BMI group (18.5 Kg/m2 ≤ BMI < 25.0 Kg/m2) and high BMI group (BMI ≥ 25.0 Kg/m2). Clinicopathological characteristics and prognosis of patients were recorded and analyzed. Propensity score matching was used to match patients in the three groups.From October 2008 to March 2015, 1210 gastric cancer patients treated with D2 gastrectomy were enrolled in the present study. Patients were divided into three groups: low BMI group (BMI < 18.5 Kg/mP < 0.05). After matching, the clinicopathological features were all comparable among the three groups . High BMI was associated with increased blood loss and operation time, and deceased number of retrieved lymph nodes . For postoperative complications, low BMI was associated with decreased rate of postoperative fever (P = 0.025). Age, BMI, tumor size, Borrmann type, pathological type, type of gastrectomy, tumor depth, LNM and tumor stage were risk factors for the prognosis of gastric cancer. Multivariate analysis showed that only BMI, tumor size, tumor depth and LNM were independent prognostic factors. The overall survival of patients with low BMI was significantly worse than patients with normal (P < 0.05) or high BMI (P < 0.05). However, the overall survival was comparable between patients with normal and high BMI (P > 0.05).There were 107 patients in low BMI group (8.9%), 862 patients in normal BMI group (71.2%) and 241 patients in high BMI group (19.95%). Before matching, BMI was inversely associated with tumor size, tumor depth, lymph node metastasis (LNM) and tumor stage (all BMI was inversely associated with tumor size, tumor depth, LNM and tumor stage. High BMI was associated with increased blood loss and operation time, and deceased number of retrieved lymph nodes. Low BMI was associated with decreased rate of postoperative fever and decreased survival. Gastric cancer is the fourth most common cancer in the world  and the Tumor patients always tend to suffer from malnutrition and lose weight because of decreased oral intake and alterations in metabolism . The incGiven this situation, the aim of the present study was to investigate the impact of BMI on the clinical outcomes of gastric cancer.This study was performed in the Xijing Hospital of Digestive Diseases affiliated to the Fourth Military Medical University. From October 2008 to March 2015, 1210 gastric cancer patients treated with D2 gastrectomy were enrolled in the present study. All patients were treated with total, proximal or distal D2 gastrectomy. The surgical procedure was based on the recommendations of the Japanese Gastric Cancer Treatment Guidelines . The posClinicopathological data including gender, age, BMI, tumor location, tumor size, Borrmann type, pathological type, type of gastrectomy, tumor depth, lymph node metastasis and tumor stage were collected. Surgery-related data including blood loss, operation time, number of retrieved lymph nodes and length of postoperative stay were recoded. Postoperative complications within 30 days including pneumonia, fever, wound disruption, wound infection, abdominal bleeding, anastomosis leakage, chyle leakage, gastric stasis, pleural effusion and ileus were also recorded through telephone and outpatient follow up. The survival of patients was followed up till November 2016 every 3 months.2), normal BMI group (18.5 Kg/m2 ≤ BMI < 25.0 Kg/m2) and high BMI group (BMI ≥ 25.0 Kg/m2).BMI was calculated as body weight (kilograms) divided by height (meters) squared. Patients were divided into three groups according to BMI level: low BMI group . Discrete variables were analyzed using Chi-square test or Fisher’s exact test. Continuous variables were expressed as median (interquartile range) and analyzed using nonparametric test. Significant prognostic risk factors identified by univariate analysis were further assessed by multivariate analysis using the Cox’s proportional hazards regression model. Overall survival was analyzed by Kaplan-Meier method. The P > 0.05). However, BMI was inversely associated with tumor size, tumor depth, LNM and tumor stage .There were 949 male (78.4%) and 261 female (21.6%). The median age was 59 years (20–87). There were 107 patients in the low BMI group (8.9%), 862 patients in the normal BMI group (71.2%) and 241 patients in the high BMI group (19.95%). The median follow-up of the low, normal and high BMI group was 22.4 (1.3–66.2) months, 25.0 (1.4–73.5) months and 25.0 (1.6–74.6) months, respectively. The associations between clinicopathological characteristics and BMI were summarized in Table P > 0.05).To reduce bias, propensity score matching was used to match patients in the three groups. After matching, there were 104 patients in the low BMI group, 416 patients in the normal BMI group and 104 patients in the high BMI group. The clinicopathological features were comparable among the three groups after matching (Table P < 0.05). The length of postoperative stay was comparable among the three groups (P = 0.179).The association between BMI and surgery-related parameters were shown in Table P = 0.025). However, BMI was not associated with other complications .The association between BMI and postoperative complications were shown in Table The risk factors for the prognosis of gastric cancer patients were analyzed using univariate analysis and shown in Table P < 0.001) or high BMI (P < 0.001). However, the overall survival was comparable between patients with normal and high BMI (P = 0.150). Further, the overall survival of patients stratified by tumor stage were analyzed. For stage I patients, the overall survival was comparable among the three groups (P = 0.753). For stage II patients, the overall survival of patients with low BMI was significantly worse than that with normal (P = 0.032) or high BMI (P = 0.023). The overall survival of patients with normal and high BMI was comparable (P = 0.458). For stage III patients, the overall survival of patients with low BMI was significantly worse than that with normal (P < 0.001) or high BMI (P = 0.004). The overall survival of patients with normal and high BMI was comparable (P = 0.783).The overall survival of gastric cancer patients stratified by BMI was shown in Fig. P = 0.001) or high BMI (P = 0.031). However, the overall survival was comparable between patients with normal and high BMI (P = 0.731). Further, the overall survival of patients stratified by tumor stage were analyzed. For stage I and II patients, the overall survival was comparable among the three groups (both P > 0.05). For stage III patients, the overall survival of patients with low BMI was significantly worse than that with normal (P = 0.003) or high BMI (P = 0.025). The overall survival of patients with normal and high BMI was comparable (P = 0.954).The overall survival was also analyzed for patients after propensity score matching Fig. . The oveBMI is a widely used parameter in clinical practice due to easy measurement. BMI is associated with a variety of cancer, including gastric cancer . A meta-The association between BMI and tumor stage was inconsistent in previous reports. Kim et al. reported that low BMI was associated with more advanced tumor stage . Chen etThe impact of BMI on intraoperative conditions were also widely investigated. Patients with high BMI was reported to be associated with increased blood loss , 20, incFrom the surgical point of view, high BMI patients was thought to be associated with increased postoperative complications due to the prolonged operation time and increased blood loss. This has been confirmed by most of the previous reports. Kulig et al. reported that higher BMI was associated with higher rates of intra-abdominal abscess and cardiopulmonary complications . Kim et It was well known that overweight and obesity was a risk factor of death in general population . However2) in our present study. We only divided patients into low, normal and high BMI groups. The impact of obesity on the clinical outcomes of gastric cancer was not independently analyzed. Fourth, it was reported that visceral fat area may be superior to BMI to predict the risk of gastrectomy. With regret, visceral fat area of patients was not evaluated in our present study.There were several limitations in our present study. First, it was a single center’s experience with limited sample size, which may result in bias during analysis. Multi-center study with larger sample size was needed to confirm our results. Second, we only analyzed the impact of BMI at diagnosis on the clinical outcomes of patients. The impact of body weight loss before surgery on the clinical outcomes of patients were not analyzed. Third, as there were only twenty-three obese patients (BMI ≥ 30 Kg/mBMI was inversely associated with tumor size, tumor depth, LNM and tumor stage. High BMI was associated with increased blood loss and operation time, and deceased number of retrieved lymph nodes. Low BMI was associated with decreased rate of postoperative fever and decreased survival of patients.


This study aimed to develop a nomogram to predict the overall survival (OS) of stage IV breast cancer patients. We searched the National Cancer Database (NCDB) for stage IV breast cancer patients diagnosed between 2010 and 2013. Predictors of OS were identified and a nomogram was developed and validated using concordance index (C‐index), calibration plots, and risk group stratifications. A total of 7199 patients from the NCDB were included in the study. With a median follow‐up of 25.7 months, the 1‐year and 3‐year OS rates were 80.6% and 52.5%, respectively. Race, age, comorbidity status, T‐stage, grade, ER/PR/Her2 status, the presence of lung/liver/brain metastasis, surgery, radiotherapy, and chemotherapy were significantly associated with OS. The developed nomogram had a C‐index of 0.722 (95% CI 0.710–0.734) and 0.725 (95% CI 0.713–0.736) in the training and the validation cohorts, respectively. The predicted survival using the nomogram is well correlated with actual OS. The nomogram was able to stratify patients into different risk groups, among which the survival benefit of local therapy varied. We developed a nomogram to predict the overall survival of stage IV breast cancer patients. Prospectively designed studies with international collaborations are needed to further validate our nomogram. Breast cancer is a heterogeneous disease with different subtypes, each having different prognoses. Accurately estimating the prognosis of each patient may not only benefit clinical decision‐making but also inform the individualized design of surgical follow‐up surveillance plans. For early‐stage breast cancer, several risk prediction models (RPM) have been developed and widely validated InclusionFemale breast cancer.Diagnosed between 2010 and 2013.American Joint Committee on Cancer (AJCC) stage IV.Confirmed pathology.No prior diagnosis of breast cancer.Exclusion criteriaFollow‐up months equal to 0.Phyllodes tumor.Unknown bone, liver, lung or brain metastatic status.Unknown ER, PR, or HER2 statusUnknown race, tumor grade, surgery, radiotherapy, and chemotherapy.We searched the NCDB database for eligible patients. Data including the site of metastasis  and ER/PR/Her2 status are only available after 2010. In this study, we only included patients with critical data available. The detailed inclusion and exclusion criteria are listed as follows:This is an epidemiological study using de‐identified data from the NCDB registries. Therefore, consent for patient participation and study publication is not required. The study approval was waived by the ethical committee of Sun Yat‐sen Memorial Hospital based on our institutional policy. This study was reported using the STARD statement guidelines http://ncdbpuf.facs.org/) Patients were categorized into two age groups based on their age at diagnosis , as the median age of the study population was close to 60. Radiation therapy (RT) was divided into two categories (with RT and without RT).The following data were collected for each patient: year of diagnosis, age, race, county, Charlson‐Deyo score, laterality, primary tumor site, tumor grade, T‐stage, histology, estrogen receptor (ER) status, progesterone receptor (PR) status, HER2 status, metastatic sites (bone/brain/lung/liver), primary surgery categorization, radiation therapy status, chemotherapy, survival month, and overall survival status. Charlson‐Deyo score is a weighted score derived from the sum of score for each of the comorbid conditions. Higher score indicates more comorbid conditions.  and R.We used the Cox regression model and the “rms” package in R to develop an OS prediction nomogram with 1‐year and 3‐year OS as the endpoints. To evaluate the discriminative ability of the nomogram, we used the Harrell's concordance index (C‐index) A total of 7199 patients were included from the NCDB database. The number of patients being excluded at each step during the patient selection was summarized in Figure The clinicopathological features of the patients are summarized in Table Prognostic factors including year of diagnosis, tumor location (Quadrants), and tumor laterality are theoretically not associated with survival, and were excluded from this analysis. We used unadjusted Cox regression and observed that race (White vs. African American), age (≤60 years vs. >60 years), Charlson score 1 or 2 vs. 0), T‐stage, tumor grade(III vs. I), ER/PR/HER2 status, lung metastasis (Yes vs. No), liver metastasis (Yes vs. No), brain metastasis (Yes vs. No), breast surgery(BCS/Mastectomy vs. No), radiation therapy (Yes vs. No), and chemotherapy (Multiagent vs. None) were significantly associated with OS. The presence of bone metastasis, N‐stage (N2 vs. N0), and histology  were not associated with OS Table . We noti vs. 0, TA nomogram was developed using the training cohort Fig. . Each prN = 5 patients in the first quartile group and were excluded), three subgroups of patients also had significant distinctions among the KM curves  benefit of surgery of 1‐yr and 3‐yr OS was 0.8% (0.3–1.6%) and 1.6% (0.7–3.0%), respectively.There is an increasing interest in stage IV breast cancer patients, as the proportion of these patients seems to be higher in recent years, when compared with the past. Systemic use of advanced imaging methods, such as PET‐CT scanning, should be the underlying reasons, and this phenomenon was called as stage migration, that is some patients who previously would have been classified as early‐stage, would be reclassified to late‐stage, due to the advanced imaging examinations. The clinical decision‐making for these patients was highly dependent on the predicted survival. However, different metastatic patterns at initial diagnosis  combined with different molecular disease subtypes  may lead to varied overall survival in these patients The value of this nomogram can be seen in the stratification analysis. As per the recommendations from current guidelines In this study, we noticed that the predicted benefits of local surgery on OS in stage IV breast cancer patients were very low (<2%). This is consistent with the Tata trial There were several limitations in this study. The first major limitation stemmed from the lack of information concerning the use of endocrine therapy and anti‐HER2 therapy. Different treatment regimens and patient responses to these therapies In this study, we developed a novel nomogram predicting the 1‐year and 3‐year OS of stage IV breast cancer patients using national cancer database. The new nomogram can stratify patients into different risk subgroups. A prospective, internationally collaborative study is needed to further validate the new nomogram.The authors have no conflict of interest to disclose.Figure S1. We used the kernel density plot to illustrate the distribution of the predicted (A) 1‐year OS and (B) 3‐year OS of our study population.Click here for additional data file.Figure S2. Patients were categorized into four subgroups, based on quartile of their predicted OS. (A) In patients with ER+/HER2‐ and bone metastasis only, the four subgroups of patients had significantly diverged KM curves. (B) In patients with visceral metastasis, ER‐ and PR‐negative diseases, only five were assigned in the first quartile subgroup (Highest predicted OS) and they were excluded for analysis. The remaining subgroups also had significantly diverged KM curves.Click here for additional data file.Data S1. Determine the training and validation cohort.Click here for additional data file.Table S1. Univariate Cox regression analysis.Table S2. C‐index of the nomogram and clinicopathological features.Click here for additional data file.


QRS waves and QT prolongation, followed by cardiac arrest. Extracorporeal cardiopulmonary resuscitation was implemented, improving circulation. Risperidone and 9OH‐RIS levels were 9.6 ng/mL and 127.6 ng/mL, respectively. Case 2: A 54‐year‐old woman was hospitalized for femoral fracture and underwent surgery. Her electrocardiogram showed bradycardia and complete AV block. Risperidone and 9OH‐RIS levels were 3.2 ng/mL and 61.4 ng/mL, respectively.Case 1: A 20‐year‐old woman suffering a suspected overdose was transported to the hospital. She presented bradycardia with wide In both cases, only serum concentration of 90H‐RIS were elevated.OH‐RIS shows pharmacological activity equivalent to risperidone, it may induce life‐threatening arrhythmia (regardless of the intake dosage). It is critical to evaluate the serum concentration of 9OH‐RIS in suspected risperidone toxicity.Arrhythmia related to risperidone has proven rare but sometimes fatal. Serum concentrations of risperidone and the metabolite 9‐hydroxy‐risperidone (9OH‐RIS) during these events are seldom documented. As 9 However, over‐prescription and inappropriate use have recently become problematic issues.Risperidone is a second‐generation antipsychotic commonly used in patients with schizophrenia. It is a serotonin 5‐HTIn 2005, the US Food and Drug Administration published a safety statement warning against off‐label use of antipsychotic drugs for dementia, stating their association with a 1.6 to 1.7‐fold increase in mortality in elderly patients.Despite this, few cases have documented the serum concentrations of risperidone and its active metabolite 9‐hydroxy‐risperidone (9OH‐RIS) during fatal arrhythmia induced by the drug. The present study describes two patients with severe arrhythmia induced by risperidone. In both cases, only serum concentrations of 9OH‐RIS were elevated. These findings suggest that the serum concentration of 9OH‐RIS is a significant indicator of risperidone toxicity.2, 43.0 mmHg, HCO3, 20.3 mmol/L; and K, 5.5 mmol/L. After activated charcoal was given, her blood pressure dropped, and the ECG showed bradycardia with wide QRS waves, and eventually pulseless electrical activity. Chest compressions were started, followed by extracorporeal cardiopulmonary resuscitation. The patient regained spontaneous circulation, and was admitted to the intensive care unit. Therapeutic hypothermia was implemented, and she was taken off extracorporeal cardiopulmonary resuscitation the following day. Serum concentrations of risperidone, 9OH‐RIS, and aspirin were 9.6 ng/mL, 127.6 ng/mL, and 756 μg/mL, respectively. Serum concentration was analyzed using the liquid chromatography tandem mass spectrometry technique. The patient was extubated on day 12, and subsequently transferred to another hospital.A 20‐year‐old woman found unconscious at home was transported to the emergency room (ER). She had a history of depression, and was taking the medications risperidone, flunitrazepam, and aspirin. It is estimated that she took 93 tablets of risperidone (122 mg), 25 tablets of flunitrazepam (50 mg), and 160 tablets of aspirin (52.8 g). Following arrival at the ER, she was immediately intubated due to respiratory depression. Her blood pressure was 80/45 mmHg, heart rate was 120 b.p.m., and Glasgow Coma Scale score was E4VTM4. Electrocardiogram (ECG) showed sinus tachycardia, with a corrected QT interval (QTc) of 455 ms. Results of blood gas analysis were: pH 7.28; pCOA 54‐year‐old woman's car plunged off a cliff and she was transported to the ER. She had no major injuries except for a right femoral fracture. She had no medical history and no medications. She underwent surgery for her leg on day 24 of admission, and was then transferred to the orthopedics ward. On day 29, her ECG monitor alarm sounded for irregular activity and the emergency physician was called. The patient was alert and had normal vital signs. A recorded ECG revealed a complete AV block. The patient was prescribed risperidone on day 12 of admission due to symptoms of delirium, and the dose was increased to 3 mg 2 days prior to the event. She was also taking famotidine and magnesium oxide. The patient was transferred to the intensive care unit for observation, and risperidone was discontinued. Her blood tests revealed normal risperidone serum concentration (3.2 ng/mL) and elevated 9OH‐RIS serum concentration (61.4 ng/mL), thereby confirming risperidone toxicity. Arrhythmia was not documented following discontinuation of risperidone.Here, we report two cases of severe arrhythmia associated with 9OH‐RIS. There are few published reports of severe arrhythmia stemming from risperidone toxicity in which the serum concentration of risperidone and 9OH‐RIS were documented Table . In the IKr, which is involved in ventricular repolarization and the QT interval. Risperidone also has the ability to inhibit the human ether‐a‐go‐go‐related gene (hERG) channel current, a recombinant channel encoded by an IKr‐cloned equivalent. Vigneault et al.hERG channel current, prolonging QT intervals. In our first case, we concluded that the high serum 9OH‐RIS concentration led to prolonged QTc and cardiac arrest. Although salicylate toxicity was initially suspected, other possibilities were investigated for the following reasons. First, the severe metabolic acidosis and respiratory alkalosis commonly observed in fatal salicylate toxicity were mild in the present case, and unlikely to cause cardiac arrest. Second, salicylate poisoning often causes sinus tachycardia, but fatal ventricular arrhythmias are rare . However, the serum potassium level was only slightly elevated. In the second case, risperidone toxicity was diagnosed based on serum concentrations and exclusion of other causes such as cardiac disease and other drug interactions. The patient's slightly hypovolemic state may have caused risperidone toxicity despite a standard dose, however this remains unclear.Risperidone inhibits the potassium ion channel current Risperidone is metabolized to 9OH‐RIS in the liver by the cytochrome enzymes CYP2D6 and CYP3A4. As the metabolite is pharmacologically similar to risperidone, the clinical effect of the drug is evaluated by the active moiety (the sum of risperidone and 9OH‐RIS). Plasma elimination half‐lives of risperidone and 9OH‐RIS in extensive metabolizers are 2.8 and 20.5 h, respectively. The half‐life for the active moiety is approximately 24 h.et al.Recent studies show that 9OH‐RIS may have a central role in adverse effects. Suzuki The technique used to analyze serum concentrations of the two compounds is not readily available in all medical facilities. However, as previously mentioned, 9OH‐RIS elongated the QTc interval in a concentration‐dependent manner. Overdose patients or patients with a high risk of toxicity may benefit from these measurements. Easier accessibility is anticipated, given the wide prescription of the drug.In both cases, we were unable to attain genotype information, and further investigation is required. However, in conclusion, we propose that the serum concentration of 9OH‐RIS is a clinically relevant indicator for risperidone toxicity. It is instructive to evaluate the serum concentration of 9OH‐RIS when risperidone toxicity is suspected.None declared.


Furthermore, there was a threefold increase in the number of subjects who preferred elastic compared with rigid handgrip interaction. Our results suggest that device compliance is an important design consideration for grip training devices.Passive rehabilitation devices, providing motivation and feedback, potentially offer an automated and low-cost therapy method, and can be used as simple human–machine interfaces. Here, we ask whether there is any advantage for a hand-training device to be elastic, as opposed to rigid, in terms of performance and preference. To address this question, we have developed a highly sensitive and portable digital handgrip, promoting independent and repetitive rehabilitation of grasp function based around a novel elastic force and position sensing structure. A usability study was performed on 66 healthy subjects to assess the effect of elastic versus rigid handgrip control during various visuomotor tracking tasks. The results indicate that, for tasks relying either on feedforward or on feedback control, novice users perform significantly better with the elastic handgrip, compared with the rigid equivalent (11% relative improvement, 9–14% mean range;  Grip force control can also be used for human–machine interfaces and teleoperation applications, e.g. control of surgical robotics  range. The questionnaire data are discrete, but ordinal, and therefore can be analysed using the same assumptions. For these tests, a χ2-test was not appropriate due to the expected small frequencies of some of the entries. Paired tests were used to compare soft and rigid interactions, while an equivalent unpaired MWU test was employed while testing across different populations (i.e. feedforward versus feedback task conditions). Only individual pairwise comparisons (i.e. no multiple comparisons) were required.To test significant differences, non-parametric Mann–Whitney Interactions between performance differences, preference and device testing order were analysed using Fisher exact (FE) testing under the null hypothesis of pairwise independence. Differences in performance between the two handgrip types was computed as a binary variable indicating whether the MME was better for soft or rigid device interaction. Preference was extracted from the questionnaire data as a binary variable indicating whether a particular subject preferred the rigid or soft device . The device testing order is already a binary variable indicating which device was tested first. Thus, all three variables can be treated as binary and therefore categorical data.Linear regression was used to analyse relationships between age and performance for each device, task and trajectory. Both ordinary least squares (OLS) and robust least squares (RLS) were used. RLS uses an iterative reweighted least-squares method based on a bisquare function allowing outliers to be either ignored or proportionally weighted when computing best-fit lines.To test the effects of gaming experience on performance, a non-parametric Kruskal–Wallis (KW) test was performed. It is worth noting that this test makes the assumption that the gaming experience data are categorical rather than ordinal. The effect of age and gaming experience on preference was analysed using FE tests. A binary age variable indicating whether a subject was young  or old (greater than 40 years), a binary gaming experience indicating whether a subject was experienced (plays games weekly or more) or inexperienced (plays games monthly or less), and a binary preference variable  were used in this analysis. As these tests proved insignificance (see Results section), no further (post-hoc) significance testing was required.3.3.1.S2C, FFPRBS, FBS2C and FBHS). For each task, a paired MWU test was used to infer whether the median difference in performance was significant and is shown for each of the four tasks. The best error was calculated in a 30 s analysis window (i.e. W = 30), which was felt to be an adequate compromise between length and rejection of spurious events. Appendix A describes in more detail reasons behind this choice of W alongside sensitivity analysis highlighting that the performance differences between the devices is not strongly affected by the choice of W.S2C = 10.3 ± 27.1%, FFPRBS = 8.8 ± 17.9%, FBS2C = 14.4 ± 26.4% and FBHS = 11.4 ± 17.7% (mean ± s.d.), indicating that the soft handgrip enabled better performance than the rigid equivalent. This relative MME difference is normalized by the MME of the rigid device to highlight the relative improvement for the soft interaction compared to the more conventional rigid handgrip interaction. This difference is consistent across all conditions (p < 0.05) with the feedback condition showing high significance (p < 0.01) when tested using a paired MWU test. Across all tasks, the relative MME difference is 11.2 ± 22.6% in favour of soft interaction.The relative pairwise difference between the MME across the two devices are FF3.2.p < 0.001). Subjects thought they performed better , enjoyed interacting more , improved more  and had better control , when using the elastic handgrip. Subjects felt they had the same level of discomfort and fatigue for both device modalities, with over 28/66 subjects experiencing no fatigue or discomfort at all.Subjects found the soft force measuring handgrip advantageous to the rigid one due to several factors. Over 62.1% of subjects preferred the soft handgrip, 21.2% preferred the rigid device and approximately 16.7% showed no preference . FE tests also showed that, for both feedforward and feedback conditions, gaming experience did not have an effect on device preference (FF: p = 0.67 and FB: p = 1.0).KW tests revealed that, for both rigid and soft handgrip interaction, there were no significant differences in performance corresponding to the level of gaming experience (3.3.2.p = 1.0 and FB: p = 0.61). Unpaired MWU revealed that performance differences between soft and rigid interaction for younger (less than 40 years) and older  subjects were insignificant across all tasks .FE tests revealed that, for both feedforward and feedback conditions, age does not have an effect on device preference . Across all eight conditions , the average R2adj value was higher for the RLS method (OLS: R2adj = 0.22 ± 0.17 and RLS: R2adj = 0.31 ± 0.11) highlighting that the presence of outliers was likely in the datasets. Therefore, further analysis was only performed using the RLS method.To understand the effect that age has on performance, linear models were computed between the age of the subjects (continuous-independent variable) and the MME during each task (continuous-dependent variable). To mitigate the effects of outliers, RLS alongside OLS was used. slope = 0.12 ± 0.05%/year), highlighting that regardless of the interaction mode or task, MME does increase with age. S2C, FFPRBS and FBS2C). However, these differences were found to be insignificant .The average slope of the RLS linear model was positive . Specifics of this association in the FBHS task highlighted that the majority of subjects who performed better with a particular device preferred that device .FE tests revealed that for three of the four trajectories, device preference was not associated with differences in performance (FF3.3.4.p < 0.001), enjoyment (Q2: p < 0.05) and control (Q6: p < 0.01). It was not influenced by the other questions regarding discomfort (Q3: p = 1.0), improvement (Q4: p = 0.12) and fatigue (Q5: p = 0.63) for which both soft and rigid handgrip devices were found to provide similar advantages , device preference was dependent upon differences in responses for three of the six questions. Specifically, preference was influenced by a different perception of performance . Further analysis of the specifics of these associations highlighted that they were due to subjects who started with the soft device performing similarly  while for subjects who started with the rigid device, the majority of subjects performed better with the soft device  during these two tasks. This indicates that practising with the soft device helped using the rigid one, but not the converse.FE tests revealed that for two of the tasks, the device testing order (i.e. soft followed by rigid or vice versa) did have an effect on performance (FFp < 0.05). Further analysis of the specifics of this association highlighted that it was due to subjects who used the soft device first being (13/25) undecided in their preference, while subjects who used the rigid device first were (28/30) in favour of the flexible device.FE tests revealed that device preference was also dependent on the order that the devices were tested, showing significance for both tasks  random trajectories especially challenging )In conclusion, our results demonstrate that, regardless of age and experience, coupling force and position through an elastic structure has positive effects in terms of performance and subjective experience during grip force control. We hypothesize that this advantage is due to the coupled movement, providing additional sensory information including (dynamic) proprioceptive and cutaneous feedback. Therefore, device elasticity is an important consideration when designing new grip measurement devices and further enables the training of hand dexterity and strength alongside functional movements. This should be considered when designing a handgrip for training and rehabilitation, or more generally as a human–machine interface.


NAFLD), the most common chronic liver disease in humans, is characterized by the accumulation of triacylglycerols (TGs) in hepatocytes. We tested whether 2′,3′,5′‐tri‐acetyl‐N6‐(3‐hydroxylaniline) adenosine (IMM‐H007) can eliminate hepatic steatosis in hamsters fed a high‐fat diet (HFD), as a model of NAFLD. Compared with HFD‐only controls, IMM‐H007 treatment significantly lowered serum levels of TG, total cholesterol, and free fatty acids (FFAs) in hamsters fed the HFD, with a prominent decrease in levels of serum transaminases and fasting insulin, without affecting fasting glucose levels. Moreover, 1H‐MRI and histopathological analyses revealed that hepatic lipid accumulation and fibrosis were improved by IMM‐H007 treatment. These changes were accompanied by improvement of insulin resistance and oxidative stress, and attenuation of inflammation. IMM‐H007 reduced expression of proteins involved in uptake of hepatic fatty acids and lipogenesis, and increased very low density lipoprotein secretion and expression of proteins responsible for fatty acid oxidation and autophagy. In studies in vivo, IMM‐H007 inhibited fatty acid import into hepatocytes and liver lipogenesis, and concomitantly stimulated fatty acid oxidation, autophagy, and export of hepatic lipids. These data suggest that IMM‐H007 resolves hepatic steatosis in HFD‐fed hamsters by the regulation of lipid metabolism. Thus, IMM‐H007 has therapeutic potential for NAFLD.Nonalcoholic fatty liver disease ( ABCA1ATP‐binding cassette subfamily A member 1AMPK5′‐AMP‐activated protein kinaseHFDhigh‐fat dietNAFLDnonalcoholic fatty liver diseaseNASHnonalcoholic steatohepatitisNonalcoholic fatty liver disease (NAFLD) is the most common cause of human liver disease worldwide and is considered to be the hepatic manifestation of the metabolic syndrome, which is closely associated with obesity, type 2 diabetes mellitus, and insulin resistance. NAFLD encompasses a broad spectrum of disease, ranging from simple steatosis with a benign prognosis to progressive nonalcoholic steatohepatitis (NASH) with inflammation and fibrosis, which can lead to cirrhosis and end‐stage liver disease. The prevalence of NAFLD has been estimated to be 20–30% in Western populations and 5–18% in Asian populations de novo lipogenesis, reduced fatty acid oxidation and autophagy, and impaired export of triacylglycerols (TGs) from liver to blood Lipid accumulation in hepatocytes occurs when the amount of fatty acid input exceeds the output, because of increased hepatocellular import of serum fatty acids, augmented IMM‐H007, also known as WS070117, is a novel lipid regulator with a structure that was discovered by investigators at the Institute of Materia Medica, Chinese Academy of Medical Science (CAMS), and Peking Union Medical College (PUMC). IMM‐H007 can regulate lipid metabolism in hamsters with hyperlipidemia and in the human hepatocellular carcinoma cell line HepG2 by activating 5′‐AMP‐activated protein kinase (AMPK), an important cellular energy sensor IMM‐H007 (WS070117), 99.7% pure (assessed by HPLC), was from the Institute of Materia Medica, CAMS, and PUMC . Primary antibodies directed against lipoprotein lipase (LPL), microtubule‐associated proteins 1A/1B light chain 3B (LC3B), and adhesion G protein‐coupled receptor E1 (F4/80) were purchased from Abcam . Primary antibodies directed against CD36, β‐actin, phosphorylated sterol regulatory element‐binding protein 1c (p‐SREBP‐1c), fatty acid synthase (FAS), stearoyl‐CoA desaturase (SCD1), Beclin‐1, sequestosome‐1 (p62), phosphatidylinositol 3‐kinase catalytic subunit type 3 (PI3K3C), RAC‐alpha serine/threonine protein kinase (AKT), p‐AKT, insulin receptor substrate 1 (IRS), p‐IRS, nuclear factor kappa light chain enhancer of activated B cells (NF‐κB), and p‐NF‐κB were purchased from Cell Signaling Technology . Primary antibodies directed against NAD‐dependent protein deacetylase sirtuin‐1 (SIRT1) and peroxisome proliferator‐activated receptor γ coactivator 1‐α (PGC1α) were purchased from Santa Cruz Biotechnology . Carnitine O‐palmitoyltransferase 1, liver isoform (CPT1) antibody was purchased from Abgent .Animals used in this study were in accordance with the relevant federal guidelines and institutional policies, and the protocol was approved by the Animal Care and Use Committee at the Institute of Materia Medica, CAMS, and PUMC . All surgeries were carried out under sodium pentobarbital anesthesia, and all efforts were made to minimize the animals’ discomfort.n = 50) were purchased from Vital River Lab Animal Technology . The animals were kept in an environment with a constant temperature of 22 ± 1 °C, relative humidity of 55 ± 4%, and 12‐h light–dark cycle (08:00–20:00). They had free access to food and water. After 1 week of acclimatization, the animals were randomly divided into five groups: a normal control group with a chow diet, a model control group with a high‐fat diet (HFD), and three IMM‐H007 groups with HFD. Two weeks later, the IMM‐H007 groups were administered orally IMM‐H007 at 25, 50, and 100 mg·kg−1, twice a day . After 12 weeks of IMM‐H007 treatment, glucose and insulin tolerance tests were conducted and the TG secretion rate was measured. MRI examinations were carried out with a 7T Bruker BioSpec imaging system  equipped with a 16‐cm horizontal‐bore magnet. The animals were then sacrificed; serum was collected for biochemical analysis and livers for histopathological examination and immunoblotting.Syrian golden hamsters  and blood samples were collected from the retrobulbar vein 0, 30, 60, 120, and 180 min later to determine serum glucose using the Accu‐Chek Performa system . In the insulin tolerance test, hamsters that had fasted for 2 h were injected with recombinant insulin (0.75 U·kg−1), blood samples were collected from the retrobulbar vein 0, 30, 60, 120, and 180 min later, and serum glucose was determined as previously described In the glucose tolerance test, hamsters that had fasted for 16 h were injected intraperitoneally with 20% (w/v) glucose , was calculated from the difference in serum TG concentrations over a given interval after P407 injection.The rate of TG secretion was measured as previously described Serum levels of total cholesterol (TC), TGs, and free fatty acids (FFAs) were determined using commercially available enzymatic assay kits . Serum concentrations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were analyzed using commercial clinical diagnosis kits , with the manufacturer's standards and protocols.Liver tissues were trimmed (to 2 mm thickness) and then fixed in 4% neutral‐buffered formaldehyde, processed, and embedded in paraffin, and 5‐μm sections were stained individually with hematoxylin and eosin , Sirius Red , and Masson (Baso) to evaluate hepatic steatosis and fibrosis.m Tris/HCl (pH 7.4), 150 mm NaCl, 1% (v/v) NP‐40, 0.1% (w/v) SDS), and centrifuged at 14 000 g for 10 min at 4 °C. Supernatants were collected, to enable determination of the concentrations of TC and TGs, using commercially available enzymatic kits [Sekisui Medical Technology (China)].Snap‐frozen liver tissues were homogenized and lysed in a buffer  and malondialdehyde  and activities of superoxide dismutase , catalase and GSH peroxidase .Snap‐frozen liver tissues were homogenized in ice‐cold phosphate‐buffered saline and centrifuged at 3500 m Tris/HCl (pH 7.4), 150 mm NaCl, 1% (v/v) NP‐40, 0.1% (w/v) SDS), supplemented with complete protease inhibitors cocktail (Roche) and centrifuged at 12 000 g for 20 min at 4 °C. Supernatants were collected for the analysis of tumor necrosis factor alpha (TNF‐α) and interleukin (IL)‐6 using commercial ELISA kits .Snap‐frozen liver tissues were homogenized and lysed in a buffer  was utilized to perform triggered respiratory gating, to obtain static images by limiting data acquisition to the end of expiration. Each hamster examined was placed in a cylindrical coil (60 mm inner diameter). Respiratory triggered 1_Localizer sequence was performed to confirm the positioning of the coil with the following parameters: repetition time (TR) = 25 ms, echo time (TE) = 2.7 ms, flip angle (FA) = 30°, slice thickness = 1 mm, data matrix = 256 × 256, field of view (FOV) = 60 × 60 mm, and number of repetitions (NEX) = 2. To avoid obvious blood vessel and subcutaneous fat contributions, T1_RARE (rapid acquisition with relaxation enhancement) imaging was used to guide the placement of the spectroscopic volume of interest (VOI) with the following parameters: TR = 500 ms, TE = 9 ms, echo spacing (ES) = 9 ms, rare factor (RF) = 4, slice thickness = 1.5 mm, data matrix = 256 × 256, FOV = 70 × 70 mm, and NEX = 8. Respiratory‐gated single‐voxel‐localized 1H‐MRS was accomplished using the point‐resolved spectroscopy (PRESS) sequence. The measurement parameters were as follows: TR = 2500 ms, TE = 16.168 ms, FA RF1 = 90°, FA RF2 = 180°, FA RF3 = 180°, points = 2048, and VOI = 4 × 4 × 4 cm3. Because the magnetic field homogenization is critical, local shimming was carried out until the line width of water reached < 50 Hz, conditioning the spectral resolution. Spectral data were processed using Topspin 6.0 (Bruker). The lipid indices were defined and calculated as shown in Table The levels of liver lipids were further measured by single‐voxel‐localized g for 20 min at 4 °C. Supernatants were collected and diluted with RIPA lysis buffer containing protease inhibitors and phosphatase inhibitors, and the protein concentration was quantified using Bicinchoninic Acid Protein Assay Kit . The proteins were separated by 10–12% SDS/PAGE, transferred to polyvinylidene fluoride membranes, and incubated with primary antibodies at 4 °C overnight, and then with appropriate HRP‐conjugated secondary antibodies for 1 h at room temperature. The immunoreactive proteins were detected by chemiluminescence  and analyzed with image j software . The internal control was parallel blotting of β‐actin.Liver tissues (100 mg) were homogenized in RIPA lysis buffer  supplemented with protease inhibitor cocktail (Roche Diagnostics) and phosphatase inhibitors . Liver homogenates were centrifuged at 12 000 t‐test (two‐tailed) was used to evaluate the differences between means of two groups, and ANOVA was used to analyze the differences among three or more groups with Tukey's or Sidak's post hoc testing. Statistical significance was assumed at P < 0.05 or P < 0.01.Data are presented as mean ± standard error of the mean (SEM). Student's High‐fat diet‐fed hamsters showed a significant increase in serum TG, TC, and FFAs compared with chow‐fed hamsters Table . TreatmeWe investigated whether IMM‐H007 has an effect on HFD‐induced steatosis in hamsters fed with HFDs. Liver histopathological evaluations showed that HFD‐fed hamsters exhibited increased lipid accumulation in liver cells, whereas treatment of HFD‐fed hamsters with IMM‐H007 resulted in attenuation of steatosis Fig. C. IMM‐H0in vivo MRS provided information about lipid composition. Compared with hamsters fed with chow diets, HFD‐fed hamsters showed significant decreases in the polyunsaturation index (PUI) and unsaturation index (UI), with concomitant increases in the saturation index (SI), suggesting a pathological balance of fatty acids consistent with a fatty liver. HFD‐fed hamsters administrated with IMM‐H007 had a significant increase in PUI and UI, accompanied by a significant decrease in SI, relative to HFD‐only controls  ratio, which is the ratio of the integral of water [4.7 parts per million (p.p.m.)] to the integral of methylene and water (1.3 + 4.7 p.p.m.) In patients with NAFLD, about 60% of liver TGs are derived from nonesterified fatty acids and 15% from the diet de novo lipogenesis accounts for 26% of liver content of TGs in patients with NAFLD. We investigated whether IMM‐H007 inhibits the process of lipogenesis. Two important enzymes are involved in hepatic de novo lipogenesis: FAS is responsible for fatty acid synthesis, thus contributing to hepatic steatosis, and SCD1 converts saturated fatty acids into monounsaturated fatty acids, facilitating the synthesis of TGs and other lipids. Hepatic expression of FAS and SCD1 was reduced significantly in hamsters treated with IMM‐H007, compared with HFD‐only animals  can lead to hepatosteatosis, and therapies that can modulate this process could have a role in resolving hepatic steatosis. We examined whether IMM‐H007 can affect fatty acid export by cotreatment of animals with P407, an inhibitor of VLDL hydrolysis that does not affect lipoprotein metabolism Consistent with our observation of decreased levels of serum transaminases, we found decreased levels of phosphorylated NF‐κB with no significant change in total levels of NF‐κB in HFD‐fed hamsters treated with IMM‐H007, compared with HFD‐only animals Fig. A. Notabl−1 cleared glucose more effectively than HFD‐only hamsters. Moreover, in the insulin tolerance test, the response of HFD‐fed hamsters that received IMM‐H007 curves was close to that of chow‐fed hamsters , compared with HFD‐only animals  ratio, reflecting reduced liver fat deposition, in accordance with biochemical data and the reduction in histologically determined steatosis, suggesting that MRS enables accurate quantification of liver fat. We also utilized MRS to identify modifications in the nature and proportions of fatty acids that are associated with steatosis in vivo MRS may have applicability for the noninvasive monitoring of nutritional status in NAFLD patients with diseased livers.Noninvasive MRS is suitable for the quantification of liver fat and identification of the nature of the fat Cordyceps militaris. Previous studies found that cordycepin has beneficial effects on the liver in vivode novo lipogenesis and fat consumption, including fat oxidation and autophagy.Although exercise and caloric restriction are efficacious for the treatment of NAFLD, they have high dropout rates. Therefore, many pharmacologic strategies have been investigated for improving NAFLD, whose common characteristic is activation of AMPK. Cordycepin is an adenosine analog that is isolated from the fungus Previous results demonstrated that SIRT1 activity is enhanced by AMPK, resulting in deacetylation and activation of PGC1α, which drives fatty acid oxidation and mitochondrial biogenesis IMM‐H007 activates fat disposal not only by stimulating fatty acid oxidation, but also by inducing autophagy, a lipolytic process in which portions of lipid droplets, or even whole droplets, are transported to lysosomes and degraded. Autophagy has an important role in the modulation of insulin resistance, and in lipid metabolism and improvements in NAFLD Our results also demonstrated an effect of IMM‐H007 on liver TG synthesis and export of TGs from hepatocytes to blood through incorporation into VLDL, which contributes to resolution of steatosis in HFD‐fed hamsters. SREBP‐1c is an isoform of SREBP, a key lipogenic transcription factor; SREBP‐1c preferentially regulates lipogenic genes involved in the synthesis of fatty acids and TGs Insulin resistance contributes to the initiation and progression of NAFLD de novo lipogenesis, and increases fat consumption and fat export from the liver. However, previous studies have shown that the leptin, adiponectin, and PPAR ligands have roles in the amelioration of liver steatosis AMPK activation by IMM‐H007 may partially explain the observed decrease in hepatic uptake of peripheral fatty acids and lipogenesis, the increase in fatty acid oxidation and autophagy of lipid droplets, and the promotion of hepatic TG export to the blood, because AMPK activation inhibits hepatic uptake of fatty acids and In conclusion, IMM‐H007 treatment in HFD‐fed hamsters improved steatosis by the regulation of lipid homeostasis in the liver, improvement of insulin resistance and oxidative stress, and attenuation of inflammation. These results demonstrate the potential of IMM‐H007 as an effective therapy for amelioration of NAFLD.HS and QW designed and conducted experiments, analyzed data, and wrote the manuscript. HZ designed experiments, wrote the manuscript, and supervised this project. LY applied for permission from the institutional review board of Materia Medica, CAMS, and PUMC . SX supervised the work presented in this manuscript.