Likely duration of survival of children described as having cerebral palsy is of considerable interest to individuals with cerebral palsy, their families, carers, health professionals, health economists and insurers. The aim of this paper is to describe patterns of survival and mortality to the sixth decade in a geographically defined population of people with cerebral palsy stratified according to the clinical description of their impairments in early childhood.Identifiers of persons born in Western Australia 1956–2011, registered with cerebral palsy on the Western Australian Register of Developmental Anomalies and surviving at least 12 months, were linked to the Australian National Death Index in December 2014. Patterns of mortality were investigated using survival analysis methods.Of 3185 eligible persons, 436 (13.7%) had died. Of that sample the 22% with the mildest impairment had survival patterns similar to the general population. Mortality increased with increasing severity of impairment. Of 349 (75%) with available cause of death data, 58.6% were attributed to respiratory causes, including 171 (49%) to pneumonia at a mean age of 14.6 (sd 13.4) years of which 77 (45%) were attributed to aspiration.For the most severely impaired, early childhood mortality increased in succeeding decades of birth cohorts from 1950s to 1990 with 20% dying by 4 years of age in the 1981–1990 birth cohort; it then decreased for subsequent birth cohorts, 20% mortality not being attained until 15 years of age. However by 20 years of age mortality of the most severely impaired born in the 1991–2000 birth cohort exceeded that of all other birth cohorts.Remaining life expectancies by age to 50 years have been estimated for two strata with more severe impairments.For 22% of individuals with cerebral palsy with mild impairment survival to 58 years is similar to that of the general population. Since 1990 mortality for those with severe cerebral palsy in Western Australia has tended to shift from childhood to early adulthood. Estimates of likely duration of survival with severe cerebral palsy (CP) continue to be of considerable interest to individuals with CP, their families, carers, health professionals, health economists and insurers. Longitudinal CP registers ascertaining all cases born within a defined geographical area form the ideal basis from which to conduct survival studies stratified by descriptions of early impairments. Many such registers now exist internationally, providing locally relevant survival statistics, however the majority are of quite recent origin and therefore can only report on somewhat limited durations of survival. Register longevity is dependent on continuous funding which can be difficult to source . In thisThe survival to June 1997 of people with CP born in Western Australia (WA) between 1956 and 1994 was described in our previous paper . MortaliMore recent CP register studies from Western Sweden  and VictThe objective of the current paper is to extend our original birth cohort by 16 years, adding births 1995–2011 and considering deaths occurring up to December 2014, thereby extending the period of observation for the earliest registrants well into the 6th decade. Survival is examined by severity of disability and across birth cohorts and compared with that of the general population.What was formerly known as the WA Cerebral Palsy Register has been incorporated into the Western Australian Register of Developmental Anomalies (WARDA) and includes persons with CP born in WA from birth year 1956 onwards. Children meeting the criteria for CP acquired before 5 years of age have been actively ascertained from multiple sources since the inception of the register in 1977 . The medFor these analyses, only those registrants surviving at least 12 months after birth were selected since many registers do not accept an incontrovertible description of CP prior to 12 months, nor would the sample be complete since infants who would have acquired the CP label had they survived will not be included. On account of this exclusion, remaining life expectancies are estimated from 1 year of age. Although the registered descriptions of impairments are those reported close to 5 years of age, the neurological damage responsible for those impairments existed before that age: at least since the perinatal period for those pre- and perinatally acquired and from the age of acquisition for the post neonatally acquired, which for half of whom was below 1 year of age .Death information was sought in the  National Death Index (NDI) to identify all deaths of WA born CP registrants who had died within Australia. WARDA sent identifiers of all CP registrants born in WA 1956–2011 to the Australian Institute of Health and Welfare (AIHW), the custodians of the NDI. For every CP registrant with a possible match to the NDI, the AIHW added the date and any recorded cause(s) of death and these were verified by WARDA. Before submitting the file to the author, all personal identifiers were replaced with a study number  and data describing the impairments and perinatal characteristics of each registrant were added.Clinical descriptors of impairments when the participants reach 5 years of age that were used in these analyses are necessarily those that have been used since the inception of the WA CP register, since descriptors commonly used today (eg. the gross motor function classification system (GMFCS)) are not available for participants registered before these descriptors existed, which constitute the majority of our sample. Severity of motor impairment at the most impaired part of the body is categorised as minimal if abnormal neurological motor signs are present but confer little functional impairment, mild if there is some functional impairment, severe if there is little or no purposeful voluntary action possible and moderate if function lies between mild and severe.The combined impact on survival of several co-existing impairments was investigated with the overall disability score (DISAB) described in our previous paper  Table 11. DISAB http://web1.sph.emory.edu/users/cdckms/exact-midP-SMR.html. Kaplan-Meier survival curves were plotted with proc lifetest (SAS version 9) by each participant characteristic including year of birth. The log rank test was used to estimate the reported significance of differences between survival curves. In each age group (1–4 years and thereafter in 5 year age bands) and in each disability score band  mortality rate  was compared with that reported in Australian life tables 1995–97 [Frequency distributions were obtained of the characteristics of participants and causes of death. Mortality rates and standardised mortality ratios (SMR) were estimated by age (up to 58 years) and DISAB, with exact 95% confidence intervals of the SMRs obtained using the online calculator Life expectancy was calculated using the method of abridged life tables , 11. LifThere were 3213 registrants on the WA CP register born in WA between 1956 and 2011. This data set was linked to the NDI in December 2014. Of these 3213 registrants 28 had died before 1 year of age. These analyses therefore consider 3185 CP registrants born in WA 1956–2011 and surviving at least 1 year, of whom 436 (13.7%) had died as of December 2014 and 2749 had not.p < 0.0001) and median DISAB decreased from 6 to 4,  p < 0.0001. Among the 95.7% with sufficient data to calculate a DISAB score, each of the scores 1 to 12 was represented, although only 13 cases (0.43%) had a score of 12, since bilateral deafness is an infrequent co-occurring impairment.Their neonatal and impairment characteristics are shown in Table Immediate causes of death by disability score and duration of survival are shown in Table p < 0.0001). Survival curves stratified by these six groups  are shown in Fig. SMRs stratified by each of the 12 possible DISAB scores are shown in Table p < 0.0001). At the same time DISAB scores tended to increase in the DISAB> = 9 stratum  p = 0.005) and decrease in the DISAB <=5 stratum regression coefficient = − 0.14  p < 0.0001 with no systematic change in DISAB distribution over birth cohorts in the DISAB 6–8 stratum (p = 0.88).The proportion of the CP population with DISAB scores 9–12 remained constant at just below 20%, but the proportion with scores 1–5 increased from one half in the 1950s to two thirds in the new millennium, balanced by a decrease in the proportion with DISAB scores 6–8  until the sixth stratum which encompassed 11 years, 2001–2011.p < 0.0004). Examination of the curves suggests the following: that registrants born in the first four year-of-birth strata (1956–1990) showed somewhat similar survival patterns: mortality rate was highest in early childhood and decreased with age until middle-age, but the early childhood rate increased in each subsequent decade. The two most recent birth cohorts (1990s and 2000’s) show different survival patterns: mortality rate in the first decade of life was lower than in the 1970s and 80s but did not decrease with age. In contrast to the first three strata, the curves suggest that those born in the 1990s experienced accelerating mortality in early adulthood such their survival to 20 years was the lowest of any year of birth decade. Births in the 2000s were too young at the census date to indicate whether this profile of accelerating mortality in early adulthood will be repeated, but their profile of mortality in early childhood overlays that of the 1990s cohort, with the suggestion of higher mortality on attaining school age. The 1980s birth cohort showed a transitional pattern: while mortality was highest early childhood (as in previous cohorts) it did not continue to decrease with age through adolescence and adulthood.Survival analysis by decade of birth of those with DISAB > = 9 is shown in Fig. p = 0.049) with mortality being highest for the 1960s birth cohort and lowest (to 14 years of age) for the most recent cohort, Fig. Survival analysis of those with DISAB score of 6, 7 or 8 showed much lower mortality rates that changed little with age. Their differences in survival patterns between the birth cohorts were estimated by log-rank test to be of marginal statistical significance  and primary hypotonia (n = 31). Mortality in those with hypotonic CP greatly exceeded that of those primarily ataxic, primarily because 11/31 with hypotonic CP had a DISAB score > =10, compared with only 2/97 with primarily ataxic CP. Limiting DISAB to the range 6–9 however still indicated significantly higher mortality (p < 0.0002) in those with hypotonic  than with primarily ataxic CP .The numbers of registrants with a disability score > 5 and primarily ataxic or hypotonic CP were small: primary ataxia (p < 0.004). However, those with a recognised post-neonatal cause tended to have more severe impairment: 54.5% (N = 145) of post-neonatally acquired CP had a DISAB< 6 compared with 64% of pre-and perinatally acquired, and 27.1% (n = 72) had DISAB> = 9 compared with 18.4%. Controlling for DISAB in multivariable Cox regression reduced the statistical significance of post neonatal acquisition to p = 0.228, indicating that their greater degree of impairment was primarily responsible for the shorter survival of those with post-neonatally acquired CP.Timing of brain damage was available for 3067/3185 (96.3%) of the sample. For 2700 (88.0%) it was considered pre- or peri-natal, for 367 (12.0%) a recognised post-neonatal cause occurred before the age of 5 years. Those with post neonatal acquisition had a statistically significantly shorter survival  deaths. Availability of cause of death data was associated with the year of death, being available for only 2 of the 42 (5%) cases dying before 1971, 48% of those dying in the 1970s increasing to 95% of those dying after 2000. Whether a cause of death was recorded was not associated with the severity of impairments.n = 187) of those with data concerning cause, principally pneumonia (82%) of which almost half (45%) were attributed to aspiration. A further 6% of respiratory deaths were attributed to choking. In addition, 5 of the 10 persons tabulated as having > 1 sufficient immediate causes of death died with complicated pneumonia.The distribution of immediate cause of death is shown in Table n = 24) did not have a satisfactorily explanatory cause. The coded ‘causes’ for this group included ‘cerebral palsy’, ‘respiratory arrest’, ‘cardiac arrest’, ‘found dead’ and even ‘senescence’. Although variable, mean DISAB was high (8.3) with a higher median score (9.5) indicating a positively skewed distribution which suggests that persons in this category may simply have been medically fragile. All 8 dying in childhood had DISAB scores > = 9, while the 5 with DISAB< 6 died in adulthood. This category was used more often in more recent deaths, accounting for 10.7% of deaths since the year 2000.The next most numerous category accounting for 6.9% (n = 21) were variable. Drowning, the most frequent cause (n = 5), was seen primarily in children. Other causes tended to be associated with deaths in adults with relatively low disability scores and may include suicides.Causes of traumatic/accidental deaths , adult services are now finding themselves in a position analogous to that of neonatal services some decades ago: they are being presented with problems with which they have very little prior experience. Neonatal services were presented with increasingly premature live births and with increasingly compromised more mature newborns. Initially survival of these infants was very poor but with increasing experience first survival improved, which was a pre-requisite, of course, to subsequent improvements in neurological outcomes in these very vulnerable patients. It has taken time to develop the expertise to successfully manage novel medical problems. Additionally, current adult medical services in Australia tend to be highly specialised and maybe ill equipped to deal with permanently disabled young people with multiple health problems who are best served by a wholistic approach to medical care and may require the advocacy of a third party. The increasing duration of survival of children with severe and multiple impairments brings with it the need to address the problems of their transition to adult services that are equipped to address their needs, yet those needs are not necessarily well understood, see below under ‘It is difficult to directly compare our results with published studies of mortality in CP due to differences in sample selection, in methods of categorising their impairments, in analytical methods, statistics reported and the birth cohorts considered. Furthermore if, as we anticipate, duration of survival with severe and multiple impairments is dependent not only on obstetric and neonatal expertise but also on the policies governing application of that expertise  as well as social factors determining the care they receive throughout the lifespan, it would be surprising if mortality rates, even if estimated using the same methods, did not vary temporally and geographically. The main effect of such factors may be anticipated to be via the distribution of types and severity of impairments observed. For example in a comparison of studies from California, UK and WA, Shavelle, Strauss and Day showed that groups of children from each study with very similar levels of motor and cognitive impairments had very similar survival curves . But detchronic lung disease which predisposes its sufferers to the recurrent pneumonia and respiratory failure seen in people with CP with oropharyngeal dysfunction. At the end of life it presents as an extremely marked susceptibility to respiratory infections during which repeated prolonged hospitalisations for respiratory support with oxygen or non-invasive ventilation may be required [All studies of CP mortality investigating cause attribute more than half of observed deaths to respiratory problems but the exact nature of those problems, which may be specific to CP, is not well defined. Most such studies mention aspiration associated with oropharyngeal dysfunction and resulting pneumonia as important factors. e.g. . These wrequired . This marequired .The increased use of gastrostomies has offered better nutrition and limited aspiration primarily to saliva only, rather than food, drink and saliva. However gastrostomy does not prevent repeated multi-day hospital admissions  and it iThere is limited evidence concerning either the prevention or treatment of oropharyngeal dysfunction and chronic respiratory disease and their presence is neither well recognised nor managed at any time in the life of a person with CP . They arThis study also found that people with CP who died of causes associated with aging in the general population such as cancer, major organ failure and circulatory problems, died at younger ages than would be seen in the total population and tended to have relatively low DISAB scores (median 6). This is consistent with the excess mortality due to ischaemic heart disease and cancer reported in adults with CP  and withInevitably this study has limitations. Deaths among any registrants who have migrated overseas would not be identified by our methods, but such migration is considered rare for Australians with significant disability. Deaths among registrants before the age of 5 years risks misclassification both of the CP status and of their DISAB score. It is possible that some may have had an unrecognised progressive disease that would not have been included as CP had they survived to recognition of the progressive nature of their disease, though this is considered very unlikely since such cases would be strenuously investigated. Those that die before the age of 5 years tend to be very severely impaired: the more severe the impairments the earlier they can be recognised reliably. It is in the milder and moderately severely impaired persons that the degree of impairment is harder to judge in infancy, and these are most likely to survive beyond 5 years. Thus misclassification of the degree of impairment of early deaths is unlikely, particularly with the stratification of DISAB.As discussed in Methods, many of the instruments now used to assess motor function in persons with CP have only become available in the last ten years. Here we are reporting on study subjects for sixty years, so for consistency we must continue with the methodology available for all subjects.The concept of an overall disability score is valuable in predicting mortality since it considers factors not encapsulated by the GMFCS, now the most commonly used single indicator of severity of impairment. While obviously correlated it is not possible to draw one to one correlations between GMFCS and DISAB. Although the current DISAB is a composite score reflecting level of several aspects of functioning, it does not capture medical vulnerability such as that associated with very severe motor, particularly oropharyngeal, dysfunction, chronic lung disease or autonomic dysregulation. Thus as a predictor of mortality DISAB requires refinement, consideration of oropharyngeal dysfunction is essential since this is far more strongly associated with mortality than is, for example, deafness and a more rigorous assessment of cognitive ability is highly desirable, but the required measures were not available for much of this study’s sample.For 22% of our CP population with the mildest impairments, duration of survival to 58 years does not differ significantly from that of the population but, as anticipated, the SMR increases with increasingly severe impairments. Nonetheless more than 80% have a life expectancy beyond 58 years and longer follow up of population based samples with detailed descriptions of impairments is recommended to obtain a more complete picture of survival with CP. For those with severe and multiple impairments early childhood mortality has tended to decrease for births since 1990 and the majority reach adulthood.


FMD) masks the true prevalence in parts of the world where the disease is endemic. Laboratory testing for the detection of FMD virus (FMDV) is usually reliant upon the collection of vesicular epithelium and fluid samples that can only be collected from acutely infected animals, and therefore animals with sub‐clinical infection may not be identified. Milk is a non‐invasive sample type routinely collected from dairy farms that has been utilized for surveillance of a number of other diseases. The aim of this study was to examine the application of milk as an alternative sample type for FMDV detection and typing, and to evaluate milk as a novel approach for targeted surveillance of FMD in East Africa. FMDV RNA was detected in 73/190 (38%) individual milk samples collected from naturally infected cattle in northern Tanzania. Furthermore, typing information by lineage‐specific rRT‐PCR assays was obtained for 58% of positive samples, and corresponded with the virus types identified during outbreak investigations in the study area. The VP1‐coding sequence data obtained from milk samples corresponded with the sequence data generated from paired epithelial samples collected from the same animal. This study demonstrates that milk represents a potentially valuable sample type for FMDV surveillance and might be used to overcome some of the existing biases of traditional surveillance methods. However, it is recommended that care is taken during sample collection and testing to minimize the likelihood of cross‐contamination. Such approaches could strengthen FMDV surveillance capabilities in East Africa, both at the individual animal and herd level.Under‐reporting of foot‐and‐mouth disease ( Foot‐and‐mouth disease (FMD) is a highly contagious disease of cloven‐hooved mammals and is of great global economic importance  assays have been described for the rapid detection of FMDV in typical clinical samples  were collected by hand from clinical and healthy cows during FMD outbreak investigations in northern Tanzania (Serengeti and Bunda Districts) between 2012 and 2015 . The OIE recommended pan‐serotypic rRT‐PCR assay was carried out on an Applied Biosystems® 7500 Real‐time PCR System, using the Superscript III Platinum® One‐Step qRT‐PCR Kit (Invitrogen™), with primers and probes targeting the conserved three‐dimensional region of the FMDV genome . In samples with a positive signal for two FMDV types, O and SAT 1 were the most common types detected, while types A and SAT 1 were identified in one sample only. It is possible that these animals were co‐infected with multiple FMDV serotypes, as has been previously described in endemic areas  of milk samples Figure . Milk saPublished reports of clinical samples from the study region indicate circulation of all four serotypes during the study period WRLFMD, c and areCT values of the lesion material samples were stronger  than of the milk samples, confirming previous observations of higher virus concentrations in vesicular lesions  were detected in both milk and vesicular fluid in animal B, but type O was not detected in the vesicular epithelium sample. As discussed above, contamination cannot be excluded as a reason for these results. Observations from paired samples indicate that, despite a weaker rRT‐PCR signal, milk can be used for detection and typing of FMDV in most individual samples.To determine if milk is a suitable alternative sample type to vesicular lesion material (epithelium/fluid) for FMDV detection and typing, both sample types collected from the same animal were tested and the results compared Table . In the MH791039) and 7815  were found to be identical  or within one nucleotide difference  to reported sequences of paired vesicular samples from the same animals  (data not shown). The nucleotide difference for animal C was a non‐synonymous change at VP1 amino acid position 204. This nucleotide difference may be explained by a mutation that could have occurred during viral replication, as sequences from the vesicular samples were obtained from virus isolated on primary bovine thyroid (BTY) cells. Upon comparison of the SAT 1‐specific primers/probe with the VP1‐coding sequence data obtained from milk and vesicular samples, it was evident that the difference in CT values between the pan‐serotypic and the SAT 1‐type specific assay may occur due to nucleotide differences at the 3’ end of the primer binding region of the typing assay. At least one nucleotide difference was identified within the SAT 1‐specific typing assay binding region in sequences obtained from animals A and B, while no such differences were observed in sequence data obtained from animals C and D. As the VP1‐coding sequence is the most variable genome region, mismatches between the primers and probes of the typing assays and the template are expected. Therefore, it is recommended to use typing assays alongside the more sensitive pan‐serotypic assay as a screening tool (Bachanek‐Bankowska et al., VP1 sequences obtained from milk samples 7805 (animal C; accession number CT values than from vesicular samples. The study also demonstrates that VP1 sequence data may be obtained from milk samples, enhancing the possibility of further, in‐depth virus characterization. Milk sampling as a targeted surveillance approach shows promise given the concordance between typing data from milk samples and confirmed reports from outbreak investigations. Follow‐on studies are required to assess the application of pooled milk in combination with herd clinical status for FMDV surveillance. In conclusion, milk is a simple‐to‐collect, non‐invasive sample type which might be utilized in targeted surveillance campaigns in FMD endemic regions. However, due to the high analytical sensitivity of molecular tests used to detect FMDV, appropriate care needs to be taken to minimize the possibility for cross‐contamination during sample collection, transport and testing in the laboratory. The use of milk as a diagnostic sample might help to address some of the potential biases of traditional surveillance methods and improve surveillance capabilities for reporting of disease at the individual and herd level in East Africa.This study demonstrates that milk could represent a valuable sample type as an alternative to the traditional diagnostic samples collected for FMD surveillance: vesicular epithelium or fluid. Milk from individual animals can be routinely collected and FMDV RNA can be detected and typed by rRT‐PCR in milk samples in a region where FMD is endemic, albeit with weaker The authors have no competing interests. Click here for additional data file.


Flexible electronics can serve as powerful tools for biomedical diagnosis and therapies of neurological disorders, particularly for application cases with brain–machine interfaces (BMIs). Existing conformal soft bioelectrodes are applicable for basic electrocorticogram (ECoG) collecting/monitoring. Nevertheless, as an emerging and promising approach, further multidisciplinary efforts are still demanded for in‐depth exploitations with these conformal soft electronics toward their practical neurophysiological applications in both scientific research and real‐world clinical operation. Here, clinically‐friendly silk‐supported/delivered soft bioelectronics are developed, and multiple functions and features valuable for customizable intracranial applications  are integrated. Advances in soft and/or flexible electronics enable powerful tools to promote developments of neurophysiology and relevant biomedical diagnosis and therapies of neurological disorders , particularly for application cases with brain–machine interfaces (BMIs).The transient supporting and controllable delivery can be enabled well with plain silk films for implantable electronic and/or optical devices.We herein develop the clinical‐friendly silk‐supported/delivered soft bioelectronics, and integrate multiple functions and features valuable for customizable intracranial applications . Compared with previously reported work,Figure2O  after in vivo degradation,In the experiments, thin layers of brain electronics (for detection and stimulation) are lithographically fabricated with the device configuration as shown in Diverse electronic devices are facilely customized toward integration of bioelectrical functions, for example, multiple electrode layers for stimulating nervous impulses and/or detecting ECoG signals. Therefore, the silk‐supported/delivered conformal brain‐integrated electronics work as a promising strategy for multifunctionlization . The PI layer on the top surface of the silk matrix and the isolating one between Au/Cr layers are customized to be ≈2 µm thick. This configuration provides sufficient mechanical support after delivery. Meanwhile, its purposely soft feature enables the spontaneously compliant wrapping and contact on complex cortex surface, as well as superior mechanical biocompatibility within soft brain tissues.2 area for in situ ECoG detection on the rat brain. In the dry state, the silk substrate sufficiently supports the thin electronics fabricated on top to keep flat and properly hard before using, facilitating the in vivo and in situ operations. To collect and map ECoG signals in/across two brain hemispheres, the left or right part of the meshes has 24 channels each and one probing channel is positioned in the middle aiming at the joint region. The electrode arrays are placed directly on the exposed brain of a rat after craniotomy, and then silk is dissolved with saline for conformally implanting . With these single‐layer electrodes, locally distributed ECoG collection is performed in statuses of resting, penicillin‐induced epileptic seizure, and subsequent suppression with silk‐delivered phenobarbital  stimulates epileptiform drastic fluctuations (epileptic spike waves) in the ECoG bioelectrical spectra. The epileptic neural impulsions spatiotemporally spread from the starting focus and propagate in the cortex. The amplitude of fluctuations in ECoG spectra highly depends on the detecting location of electrode channels. The first three ECoG spectra in Figure Figure In Figure FigureWe investigate the ECoG signal collection via these conformal brain‐integrated electronics, and their configurations are specifically tailored and optimized toward superior bioelectrical detecting performances in vivo Figure2. The 2 areas for ECoG monitoring of different statues . For static analysis in theta and beta wavebands, the SNR of collected epileptic ECoG signals is consistently improved along with the increase of channels  on the collection and subsequent analysis of ECoG data, we compare the electrode arrays with 25, 49, and 100 channels evenly distributed in 1 × 1 cm2 by using well‐established lithographical techniques. But the huge amount of data produced during ECoG or other neural detection/monitoring brings about serious burdens of collection and analysis, in terms of processing time and hardware resource, especially impeding in situ and real‐time application cases.2 area . The time‐dependent sequence of ECoG maps in Figure The neural activities are spatiotemporally dynamic in the brain, as well as their relevant bioelectrical impulses.−1 at 30 Hz  capability. The long‐time high‐frequency neural impulses during epileptic seizure usually cause damages to the brain. So, faster release and effect of drugs  onto the brain, compared with traditional methods via intravenous injection and blood circulation, are in significant favor of the epilepsy treatments. Silk has versatile capabilities in stabilization and controllable release of medicines, especially, along with superior processability enabling the parallel monitoring of the drug‐delivery processes.z Figure b. AccordTo parallelly real‐time monitor the drug‐release process, holographic micropatterns are designed and imprinted as DOEs on the silk film. As‐needed therapeutic molecules  can be facilely loaded by aqueous blending and well stabilized in the silk pad fabricated with DOEs . The phenobarbital‐releasing processes are associated with silk dissolution, structural collapse of the DOEs, and the fading and blurring of the diffracted optical pattern  already encoded and represented in the brain.Compared with pathological epileptic cases associated with intense neural impulses, the models for neural decoding here produce ECoG with minor differences. To clearly and intuitively identify the brain bioelectrical activities in correspondence to different statuses/stimuli, the information needs to be further abstracted and analyzed from the ECoG spectra  and the ensemble patterns in Figure Constructing the purposely soft bioelectronics with well‐tailored biocompatible material and device configuration accommodates their biointerfacing, especially, for neural tissues or organs like brains with kPa‐level moduli and convoluted topography. The soft/flexible feature is indispensably applied in both conformal BMIs hereThe surrounding tissues hamper the accurate unfolding and visible positioning of electroprobes delivered in the cortex, which relies more on their spontaneous processes after injecting. However, the conformal BMIs here are customized with array layouts for specific cases, and have inherent convenience in manageably localizing onto targeted detecting spots as needed. This facilitates their practical and clinically applicable utilizations. By taking epilepsy as an example here, the seizure bioelectrically starts from one spot in the brain, and the impulses propagate and finally spread over the entire cortex across two hemispheres. Its ECoG investigations and other cases, for instance, of local brain surgeries  require precise and controllable localization, as well as a relatively large monitoring area. Without enormously increasing time and hardware resources, the customization of evenly or unevenly arrayed electrodes enhances ECoG monitoring performances specifically for applications in complex encephalic environments.These soft and/or flexible BMI strategies, including the conformal cortex‐surface electrodes and injectable in‐cortex electroprobes, are integrated with the ingenious supporting and/or delivering with aqueous or resorbable/degradable solid matrices.Previous investigations of soft conformal biointerfaces mainly perform ECoG signal collections for ability demonstration.Silk Preparation: Bombyx mori silk fibroin was prepared with the established protocols. Bombyx mori cocoons were boiled in 0.02 m Na2CO3  aqueous solution for 30 min, and then rinsed with distilled water for three times (30 min per time) to remove the Na2CO3 and sericin. After drying in air for ≈12 h, the degummed cocoons were dissolved in 9.3 m LiBr  solution at 60 °C for ≈4 h. This solution was dialyzed for 2 days in distilled water by using Slide‐A‐Lyzer dialysis cassettes . Subsequently, the solution was centrifuged two times for 20 min at 18000 rpm. The final silk concentration was determined to be about 6–7 wt% by measuring the volume of the solution and the final dried weight.Device Design and Fabrication—Fabrication of Single‐Layer Device: The wet oxidation process was used to create a 2 µm thick silicon oxide as the sacrifice layer on a silicon wafer. Then, it was spin‐coated with a 2 µm thick layer of PI. After patterning a 3 µm layer of AZ‐100 photoresist on PI by photolithography, Cr/Au patterns (150/1500 Å) were electron‐beam evaporated. Another 2 µm thick PI layer was spin‐casted on the metal layer, followed by the sputtering process of aluminum . The photoresist (AZ‐100) mask pattern was photolithographically made on Al to etch out Al patterns, in the acid corrosive liquid (a mixture of hydrochloric and acetic acid). With these Al patterns as the mask, PI layers were then etched into patterns with microwave plasma. The meshed structures and exposed pads were made by applying two different masks and etching depths. The soft electrodes were separated from the wafer after etching off the left Al with acid corrosive liquid and the SiO2 sacrificial layer with buffered oxide etch (BOE) containing hydrofluoric acid and ammonium fluoride). These soft electrodes were transferred onto dry silk films, and rinsed with acetone to enable firm attachments. Finally, they were thermally pressed (170 °C and 0.6 MPa) to connect the soft electrodes with a flexible printed circuit (FPC) by using ACF cable.Device Design and Fabrication—Fabrication of Multilayer Device: Step 3 in Figure S3 (Supporting Information) was repeated to integrate one or more electrode layers with various functions. For instance, the electrodes used in Figure S6 (Supporting Information) were integrated with electrical‐stimulating probes. Refer to the Supporting Information for more detailed descriptions on single‐layer and multilayer devices.Epilepsy Model: Intraperitoneal penicillin injection in a Sprague–Dawley rat induced the model of multifocal epilepsy. Cortical penicillin injection induced the epileptic model with the single focus at injecting spot .ECoG Animal Experiments and Ethic Documents: Experiments were conducted in accordance with the ethical guidelines and with the approval of the Huashan Hospital. ECoG recording was operated with the Blackrock Cerebus system. The sampling frequency of original date was 10 kHz and transcoded to MAT formats at 1 kHz.ECoG Data Analysis: Spectrogram analysis , ‘butter'),” where a and b are the cutoff frequencies for each frequency band. The fast Fourier transform was applied to the recorded ECoG signal, and the resulting frequency resolution was 0.05 Hz.The PSDs of recorded ECoG signal Figures b and 3c In the SNR analysis Figure c, the noµ of the amplitudes of all the channels in the electrode array. CVs were calculated for each recorded time point during the experiment; the statistics shown in Figure In the present analysis, CV is defined as the ratio of the standard deviation σ to the mean Z‐scored for eliminating the variabilities of different electrodes, and the signal's amplitude for each electrode was then calculated with a 0.1 s time window. In Step 2, the amplitude of each electrode was arranged according to its physical location, and the topographic maps of the signal's amplitude were visualized as interpolated maps in a 0.01 mm spatial resolution.Topographic maps of signal's amplitude in Figures The global maximum point was assigned within the first 10 s after the injection as the estimate onset site of the epileptic seizure, and the estimate error was then calculated as the spatial distance between the estimate onset site and the actual injection position, as shown in Figure PCA was applied for demonstrating the approachability of the proposed electrode array in the brain decoding project. The PSDs of the recorded ECoG signal in all three frequency bands  were served as the input of the PCA method. The results of PCA analysis were visualized in a 3D space based on the first three principal components, as shown in Figure Drug Loading/Releasing via Silk Matrix: Needed medicines  were blended into silk proton solution and the aqueous hybrids were casted into easy‐to‐use films and/or pads. The dosage of medicines was adjusted by controlling the amount of the drugs mixed/loaded, according to specific cases.DOE Design and Fabrication: To generate diffractive diffusers, numerical simulations were performed by the commercial software, namely, LightTrans VirtualLab 5. Diffractive diffusers were decided and the scattering of light was produced into an arbitrary 2D light pattern. This light‐intensity pattern was conversed into GDSII format and used as the mask to fabricate DOEs. The working wavelength of the input beam was set at 450 nm, and the optical setup was selected as paraxial far‐field. The construction of silk DOEs was introduced in the previous work, which described more details.Fabrication of Silicon Masks: SiO2 was thermally grown with a thickness of 600 nm on the silicon wafer. A spin‐coated layer of AZ‐100 photoresist was photolithographically patterned as the mask for the following reactive ion beam etching of exposed SiO2. After photolithography, the residual photoresist was removed by microwave plasma treating by a wet etching process using H2SO4.Animal Experiments (Silk‐DOE Degradation): Rats (6–8 week old) were anesthetized with an intraperitoneal injection of chloral hydrate . After the craniotomy, electrode devices were attached to the cortex surface for the real‐time ECoG monitoring (more details are provided in the Supporting Information). According to the epileptic symptoms, silk films with proper dosages of drugs are directly positioned on the surface of the cortex . After dropping the saline solution, the loaded therapeutic molecules were released gradually along with the dissolution of the silk matrix. A 532 nm laser beam was projected onto the silk DOEs with an incident angle of around 10°–20°, and the clear optical pattern appeared after reflecting. The holographic optical pattern changes from clear to blurred during the silk dissolution and drug release.Statuses for Neural Decoding: 1) Idle: the rat was tested in quite a dark environment. 2) Visual: the rat was stimulated with a white light‐emitting diode (LED) with ≈7500 lux illuminance. Ten times of stimulation (the 40 s resting after 10 s illumination per time) were performed after which the rat was in the resting state. 3) Electrical stimulation (E‐stimulation): ten times of current stimulations (the 30 s resting after 1 mA current stimulation for 2 s per time) were applied through the stimulating electrode integrated into the conformal BMIs at the marked spot in the third ECoG map of Figure The authors declare no conflict of interest.SupplementaryClick here for additional data file.


In addition to the demand for stimuli‐responsive sensors that can detect various vital signals in epidermal skin, the development of electronic skin displays that quantitatively detect and visualize various epidermal stimuli such as the temperature, sweat gland activity, and conductance simultaneously are of significant interest for emerging human‐interactive electronics used in health monitoring. Herein, a novel interactive skin display with epidermal stimuli electrode (ISDEE) allowing for the simultaneous sensing and display of multiple epidermal stimuli on a single device is presented. It is based on a simple two‐layer architecture on a topographically patterned elastomeric polymer composite with light‐emitting inorganic phosphors, upon which two electrodes are placed with a certain parallel gap. The ISDEE is directly mounted on human skin, which by itself serves as a field‐responsive floating electrode of the display operating under an alternating current (AC). The AC field exerted on the epidermal skin layer depends on the conductance of the skin, which can be modulated based on a variety of physiological skin factors, such as the temperature, sweat gland activity, and pressure. Conductance‐dependent field‐induced electroluminescence is achieved, giving rise to an on‐hand sensing display platform where a variety of human information can be directly sensed and visualized. We envision that multifunctional physiological skin display can be accomplished when the epidermal layer itself acts as an interactive display by replacing one of electronic components of the device by human skin.The development of electronic skin (E‐skin) capable of mimicking the human skin representatively, including the sensing of a variety of delicate physiological changes of the epidermal stimuli, is of significant interest as an important human–machine interface that can play a key role in the numerous biomedical applications of human‐activity monitoring and personal healthcare.Herein, we demonstrate a simple but robust interactive skin display with epidermal‐stimuli electrode (ISDEE) capable of simultaneous sensing and display of multiple epidermal stimuli on a single device. Our ISDEE with a simple two‐layer architecture consists of a topographically patterned elastomeric polymer composite with light‐emitting inorganic phosphors upon which two electrodes are placed with a certain parallel gap. When an ISDEE is directly mounted on the human skin, the skin surface by itself serves as a field‐responsive floating electrode of the display working under an AC. The AC field exerted on the epidermal skin layer depends on the conductance of the skin, which can be modulated as a function of a variety of physiological skin factors, such as the temperature, sweat gland activity, and pressure. Conductance‐dependent field‐induced electroluminescence is achieved, giving rise to an on‐hand sensing display, in which we are able to directly sense and visualize multiple types of human information including the temperature, sweat gland activity, and pressure as well as fingerprint.Figure2 and 5 µm, respectively, as evidenced in the scanning electron microscope (SEM) results shown in Figure Our ISDEE was conveniently developed by fabricating an elastomeric poly(dimethyl siloxane) (PDMS) composite with periodic arrays of topological micropyramids in which light‐emitting inorganic ZnS:Cu microparticles are embedded with the alumina layer for their surface passivation, followed by the deposition of two parallel PEDOT:PSS electrodes on the composite, as shown in Cair) indicates the initial capacitance between the two in‐plane PEDOT:PSS electrodes, whereas the variable one (Cs) and epidermal resistor (ZE) describe the active capacitance with the area of the electronic‐epidermal contact .The AC field applied between the two parallel electrodes has little effect on the composite owing to the in‐plane electric field. When a composite with two parallel electrodes is placed on epidermal skin, which is naturally conductive, the skin serves as a floating electrode, allowing for a sharing of the electric field, giving rise to a vertically driven electric field developed in the two overlapped areas on the AC field between the two electrodes. Under these circumstances, our device can detect either a change in capacitance or impedance depending upon a variety of vital skin information. The device scheme and electronic circuit diagram in Figure The significant benefit of our device lies in the fact that all epidermal stimuli are visualized in EL arising from solid‐state cathode luminescence of ZnS:Cu particles embedded in the PDMS, in addition to electrical detection. A change in either the capacitance or the impedance with epidermal stimuli can vary the electric field upon AC operation, giving rise to a change in EL intensity. The generation of an effective electrical field using the epidermal stimuli electrode of our ISDEE was confirmed through an electrical field calculation based on a finite element analysis (FEA), the results of which are shown in Figure FigurePrior to monitoring the pressure exerted on the human skin using our ISDEE, we examined the pressure‐sensing performance of a parallel‐type AC device with a floating indium tin oxide (ITO) electrode instead of skin, as shown schematically in Cs) becomes dominant . The current of ≈2.4 mA was detected upon every contact event, corresponding to the unharmful current level. Because our ISDEE contains an epidermal stimuli electrode whose conductance can be varied with both body temperature and sweat, the information can be monitored in terms of the impedance change as long as the AC field exerted on the ISDEE is conductance‐dependent. To prove this, we examined how the sensing performance of a parallel‐type device is conductance‐dependent with a PEDOT:PSS floating electrode, whose conductance varies with the amount of dimethyl sulfoxide (DMSO) mixed with PEDOT:PSS.Z) changes of parallel‐type AC devices with the floating PEDOT:PSS electrodes containing different amounts of DMSO were examined as a function of AC frequency and the results as shown in FigureA bottom electrode was readily replaced with an epidermal stimuli electrode by patching a bilayered topological composite with two parallel PEDOT:PSS electrodes placed on human skin, giving rise to an ISDEE, as shown in Figure −1 and [Na+] concentrations in the electrolyte solutions with relevant concentrations of 10 × 10−3 –160 × 10−3m with a sensitivity of ≈0.19% mm−1, respectively. When the ISDEE was touched on the surface of a glass cup filled with hot water, the temperature of the water was transferred to the skin electrode, giving rise to a change in impedance as well as EL upon the AC field. The emissions became brighter with the surface temperature, as shown in Figure +] 160 × 10−3m), the impedance of the device was abruptly reduced, and the original value was recovered when untouched. Multiple sweat sensing was accomplished with reliability. In addition, the concentration of sweat can be clearly visualized using EL, as shown in Figure The detection and visualization of the change in conductance of a floating electrode in terms of the impedance and EL, respectively, allowed us to utilize our ISDEE as a sensing display for both body temperature and sweat gland activity, which is sensitive to skin impedance under an AC field arising from the reorientation of lipids in the sweat glands underneath the epidermis depending upon the salt concentration in sweat. As a result, the skin impedance decreases with both body sweat and temperature. For the demonstration, an ISDEE was fabricated using a finger epidermal stimuli electrode, as shown in the photographs of Figure FigureFurthermore, our ISDEE offers a useful way to achieve the direct imaging of a 2D conductive biological information when an epidermal stimuli electrode contains a 2D pattern, such as a naturally conductive fingerprint, as schematically shown in −1, 0.19 % mM−1, and 11.63 kPa−1 for sensing temperature, sweat gland activity, and pressure, respectively, as well as a direct visualization of these epidermal stimuli. The ISDEE also allows for direct imaging of fingerprint patterns with a high resolution while achieving sensitive capacitance detection. The suitability of our extremely simple, but multimode, multifunctional skin display platform with high sensing performance  can be expanded for numerous emerging biomedical applications of human‐activity and health‐monitoring systems.In summary, this study presented a novel single device, ISDEE capable of visualizing a variety of body information such as touch, body temperature, and sweat with the simultaneous sensing of either the capacitance or impedance. The ISDEE was developed using a topographically surface‐structured elastomeric PDMS composite containing light‐emitting ZnS:Cu particles with two parallel PEDOT:PSS electrodes attached on a normal epidermal skin surface. The utilization of an epidermal skin layer as one of electrodes not only simplifies the device architecture (a bilayered structure), but also is capable of both sensing and displaying sensitive. First, the device visualized tactile sensations and finger‐bending motion in EL under an AC field while detecting such elements based on a change in capacitance. Furthermore, both body temperature and sweat sensitive to the conductance of the epidermal‐stimuli electrode were monitored based on changes in AC impedance through a direct visualization in EL. A single ISDEE exhibited the multiple sensing performance of 0.49 % °CMaterials: Green ZnS:Cu microparticles (D512C) were purchased from Shanghai KPT Co. PDMS and crosslinkers were purchased from Dow Corning. The PEDOT:PSS electrode (Clevios PH1000) was modified through mixing with 5 wt% DMSO and 1 wt% Zonyl surfactant (FS‐300 fluorosurfactant from Aldrich) with respect to PEDOT:PSS, which promoted the wetting of the ZnS:Cu/PDMS composite layer on an active layer. The 3M VHB tape  used was purchased and applied as received. Trichlorosilane (FOTS) was purchased from Sigma‐Aldrich. All other materials were purchased from Aldrich and also used as received.Fabrication of an ISDEE: An interactive sensing display was developed using a parallel‐type AC device architecture, as illustrated in Figure 2 and 5 µm, respectively. The micropatterned Si mold was treated by O2 plasma at 40 W for 3 min before deposition of a FOTS solution, which facilitated the removal of a ZnS:Cu/PDMS composite layer from the Si mold. The ZnS:Cu/PDMS composite was prepared by mixing the ZnS:Cu powder with a PDMS liquid and a curing agent (Sylgard 184) with a weight ratio of 10:1. A liquid solution was spin‐coated on the micropatterned Si substrates at 2000 rpm for 120 s, and subsequently annealed at 80 °C for 12 h, followed by UV treatment for 20 min. High‐conductivity PEDOT:PSS was modified by mixing it with 5 wt% DMSO and a 1 wt% Zonyl surfactant with respect to PEDOT:PSS. A PEDOT:PSS layer of the modified solution was then spin‐coated onto the composite film. An ≈200 nm thick PEDOT:PSS film was subsequently annealed at 100 °C for 15 min in an ambient atmosphere. In addition, the conductive PEDOT:PSS layer was treated as separate electrodes with an air gap using reactive‐ion etching (RIE). Both the composite and PEDOT:PSS layers were peeled off from the Si molds and mechanically transferred onto a 3M VHB film.An ISDEE characterization: The cross‐sectional morphology and thickness of the ZnS:Cu/PDMS composites were characterized using a field‐emission scanning electron microscope (FESEM) (JEOL‐7800F), as shown in Figure The authors declare no conflict of interest.SupplementaryClick here for additional data file.SupplementaryClick here for additional data file.SupplementaryClick here for additional data file.


Static‐lattice atomistic simulations, in vacuum and solvent phase, have been recently employed to quantify the “in vitro—in vivo—in silico” performance‐correlation profile of various drug delivery systems and biomaterial scaffolds. The reactional profile of biopolymers was elucidated by exploring the spatial disposition of the molecular components with respect to the formulation conditions and the final release medium. This manuscript provides a brief overview of recently completed and published studies related to molecular tectonics of: (a) the nanoformation and solvation properties of the surfactant‐emulsified polymeric systems; (b) the formation and chemistry of polyelectrolyte complexes; (c) the effect of a plasticizer and/or drug on the physicomechanical properties of biomedical archetypes; (d) the molecular modeling templates to predict stimuli‐ and environmentally esponsive systems; and (e) the polymer‐mucopeptide complexes and intermacromolecular networks. Furthermore, this report provides a detailed account of the role of molecular mechanics energy relationships toward the interpretation and understanding of the mechanisms that control the formation, fabrication, selection, design, performance, complexation, interaction, stereospecificity, and preference of various biopolymeric systems for biomedical applications. Conversely, there are in silico only studies providing the theoretical knowledge of various material archetypes with only few being tested at the in vitro and fewer at the in vivo level. In addition, the computational methods applied in the advanced in silico studies are very expensive and extensive in terms of time and funding.The elucidation of mechanism(s) inherent to the performance of biopolymer‐based complex assemblies presents a significant challenge to pharmaceutical and biomedical scientists around the world with most of the studies 1.1V∑ is related to total steric energy for an optimized structure, Vb corresponds to bond stretching contributions , Vθ denotes the bond angle contributions , Vϕ represents the torsional contribution arising from deviations from optimum dihedral angles, Vij incorporates van der Waals interactions due to nonbonded interatomic distances, Vhb symbolizes hydrogen‐bond energy function, and Vel stands for electrostatic energy.The MMER model for the energy factor in various molecular complexes can be written as:Total, was calculated as the difference between the total potential energy of the complex system (A/B) and the sum of the potential energies of isolated individual molecules , as follows:In addition, the total potential energy deviation, ΔE2surfactant‐evaporation (ESSE) and 2) emulsion‐solvent‐evaporation (ESE). The MMER report of these complex colloidal phases concluded that the presence of a surfactant such as sorbitan monooleate can provide the much needed conditions for the formation of uniform polymeric nanoparticles. In the ESSE paradigm, the presence of surfactant led to an increase in thermodynamic energy at the solvent/particle interface and hence the coagulation and aggregation of the nanosystem was prevented. In addition, the electrostatic and steric repulsions in case of ESSE were in the range of 1,000 and 200 kca/mol, respectively, under solvent phase simulations. Similarly, alginate nanoparticles were prepared using rigidification–gelification approach with or without adding a surfactant: (a) reverse‐emulsion‐cationic‐gelification (RECG) and (b) reverse‐emulsion‐surfactant‐cationic‐gelification (RESCG). In addition to the thermodynamic shielding and repulsions discussed above, the presence of surfactant in RESCG provided a hydrated palisade layer structure which played a major role in crosslinking induced stabilization of the nanosystem termed as—“crosslinking stabilized–stabilized emulsion.” The presence of this hydrated layer increased both the polarizability and refractivity coefficient of the RESCG matrices leading to the formation of a rigidified structure with least probability of colloidal aggregation or flocculation  directly corroborated with the ex vivo internalization findings.The formation and formulation of nano‐based systems can be achieved either through relatively simple self‐assembly (nanoliposomes or nanopeptides) or via complex emulsification‐homogenization (polymeric nanoparticles). In either case, the stabilization of the nanosystem so formed is of utmost importance and can be achieved in several ways such as by using a surfactant, a polymeric stabilizer  or even via crosslinking‐co‐rigidification of the polymeric platform.575, PEG2000, and PEG4000) and were then loaded with insulin as the model bioactive. As explained above, PEG provided the much needed hydrophilicity to the lipophillic PLA matrix and hence nanoformation within the pluronic‐based aqueous phase. Similar to CHOL, the PEG molecules played the space‐filling role and hence led to the stabilization of nonbonding hydrophobic interactions leading the efficient encapsulation of insulin in the nanomatrix. Interestingly, when MMER was applied to study the release of insulin from the nanomatrix, the presence of aqueous phase (with no cosolvent or surfactant present) hydrated the PEG component leading the entry of water into the nanomatrix and hence disturbing the hydrophobic forces thereby releasing the encapsulated bioactive. However, this concept failed in case of low molecular weight PEG‐diacrylate where the drug release was least on weight basis. The MMER conducted for all three variants in aqueous medium concluded that the insulin showed molecular interactions with the functional groups (–COOH and –NH2) present in the polymer matrix. This further confirmed that insulin released from PLA‐PEG575 matrix will be slowest as low molecular weight PEGDA will have more NH2 functional end groups than the higher molecular weight ones.On similar grounds, DSPE‐PEG/DSPC‐based nanoliposomes with cholesterol (CHOL) as the lipidic component were reported earlier. The presence of methoxy‐PEG moiety led to the formation of H‐bonding within the phospholipid complex. However, this still was not sufficient to form a thermodynamically stable nanosystem. As determined by the 3D geometrical conformation and stabilization via molecular modeling, the addition of CHOL provided the much needed space filling properties to the ternary system wherein the van der Waals space of the molecular complex contributed to matrix stabilization. This change in H‐bonding dominated system to hydrophobically stabilized system was further responsible for the self‐assembly of the complex into nanoliposomes (nanoformation) when hydrated in phosphate buffered saline.33. In addition, the molecular dynamics simulation supported the energy stabilization and it was concluded that “the potential energy decreased with an increase in the kinetic energy, obeying the well‐known behavior of high underdamping harmonic oscillator.”Polyelectrolyte complexes, as the name suggests, are complex molecular architectures composed of oppositely charged molecules. As the charged functional groups are “consumed” in the process, the inherent solubility and functionality of the individual molecules are reduced and hence an insoluble but hydrated and swellable matrix is formed.3+ (CHT and HPAAm) and –COO− (PEC and HPAAm) functional groups formed the TPIQ network via structure‐selective binding of saccharidic moieties. The in silico results concluded that the geometrical adjustment of polymeric chains to form the ionic complex is due to the minimization of Coulombic attractions and van der Waals forces. This further confirmed the in vitro controlled release of a highly soluble drug (diphenhydramine) due to matrix curing and formation of a “deforming‐type” matrix.Bawa and coworkers reported a molecular model of a tripolymeric ionic quadrilateral (TPIQ) wherein chitosan and pectin formed the cationic and anionic counterions, respectively. The third polymer employed was a partially hydrolyzed polyacrylamide (HPAAm) which acted as an anionic molecule as well as a cationic molecule in close vicinity of chitosan (CHT) and pectin (PEC), respectively. The molecular modeling simulations presented a van der Waals space overlap and the hydrogen bonding between the interaction molecules confirmed that –NH3+ of mucin and –COO− of pectin chains – overcoming the torsional barriers required for a stable network. It was further established that this interaction is concentration dependent and saturation of functional groups can be achieved by carefully manipulating the biomaterials' quantities.In a very important study, a mucopeptide was employed as an excipient to form a bimolecular complex with pectin. Although there were several earlier reports discussing the interactions of pectin with mucin, the molecular interactions inherent to this complex were not yet known or elucidated. The researchers via MMER established that there might be a possibility of formation of a blend‐co‐complex within this proteo‐saccharide matrix. Although the –COOH functionalities of the molecules lead to steric repulsion and a strained network, this initiated the much needed “neighboring” of the counterions: –NH4Polymeric fibers provide distinctive advantages in terms of size selection and mechanical properties which further define the final biomedical application. For example, nanofibrous mats are widely employed for wound dressing and oral drug delivery, microfibers for sutures, and macrofibers for periodontal diseases. For these fibers to perform optimally mechanically, addition of plasticizers is a common practice and follows the same principles as for the plasticization of polymeric films. However, given the large surface area and fine diameter size of the fibrous systems, the addition of any additives needs to be carefully controlled. For example, in case of electrospun nanofibrous systems, the electrospinning process involves careful selection of polymers and additives which in in turn affect the processing variables. As the final size of the fibers is in the range of nanometers with high surface area, addition of even a small quantity of drug may lead to reassignment of processing variables.2),As opposed to nanofibrous mats, micro‐ and macro‐fibers are fabricated using the extrusion‐gelification technique. The macrofibers in particular are used individually and afford different set of challenges such as holding the fiber using a tweezer  or simply implanting around a tooth for localized periodontal drug delivery. Johnston and coworkers, described crosslinked‐co‐plasticized, drug‐loaded, alginate fibers for localized periodontal drug delivery.Furthering the modeling of plasticizers within polymer matrices, Cooppan and coworkers explained the importance of a solid plasticizer's concentration on the optimal performance of a Eudragit E100‐based memblet system. The MMER obtained from solvent system simulation confirmed that addition of PEG4000 at a very high concentration (60% wt/vol) may lead to formation of charged regions with less solvent accessibility. These charged regions may further distort the electrostatic balance of the polymeric matrix causing repulsion and a strained network. However at 30% wt/vol PEG4000 concentration, the PEG‐enclatherated polymethacrylate system was comparatively more geometrically stabilized with defined viscoelastic regions and consistent drug release profile.54‐stabilized pectin matrix. The matrix provided localized delivery if mesalamine in the colon environment and under the influence of colonic enzymes polygalacturonase and β‐glucosidase. The colonic enzyme fragments employed in the study were generated via deduction of information corresponding to the active catalytic amino acid sequences for human acid β‐glucosidase and pectin Lyase C. The MMER data suggested that the enzymatic sequences interacted with the functional moieties of the polysaccharide molecules and relaxed the close interatomic contacts leading to degradation of the tablet matrix and hence release on the drug in the colonic environment.Enzyme responsive drug delivery: Bawa and coworkers described a stimuli‐synchronized matrix for localized colonic delivery of an anti‐inflammatory drug. The matrix systems were composed of tripolyphosphate crosslinked chitosan dispersed within a BaSOElectroresponsive drug delivery: Indermun and coworkers developed a bipolymeric interfacially plasticized electroresponsive hydrogel composed of a polyacrylic acid‐poly (PAA‐PVA) semiinterpenetrating polymer network impregnated with poly(ethyleneimine) and 1‐vinylimidazole as electroactive moieties. The molecular mechanics simulations were carried out under solvent conditions and electrostatic charges were applied three‐dimensionally to the matrix system. The researchers theorized that polymers undergo a very complex electro‐induced organization and then re‐organize when electrical stimulation was removed. The jump‐diffusional behavior shown by the electroactive molecules played a major role in drug release on the application of electric field . Hyaluronan (HYA) polymer chains in particular showed geometrical variations and interactions with the hydroxyl ions  dissolution and/or degradation profiles and the arrangement of these selected entities into a layered or multicomponent platform.Stimuli and environmentally responsive drug delivery systems form an important aspect of current drug delivery strategies given the “delivered only when needed” characteristic of these specialized platforms. These systems can be easily, but nonconclusively, classified as thermo‐, pH‐, electro‐, light‐, ion‐, oxidation‐, and enzyme responsive.Molecular modeling studies of such complex systems are very limited in the literature. The major limitation of achieving the “responsiveness” in silico stems from the unavailability of modeling platforms for perfect environmental simulation and control and need innovative solutions to elucidate the responsive behavior.6This section details a series of mucoadhesion and interaction molecular modeling studies carried out by the authors over the years (2010 onward; Table 7The above discussion and cited literature proved that not‐so‐complex and time‐efficient molecular mechanics simulations can provide an in depth account of the bonding and nonbonding interactions occurring within a biomedical device or system fabricated using biopolymers. The static‐lattice atomistic simulations and MMER also confirmed that there is a direct relationship between the in silico findings and the in vitro and/or in vivo results and hence atomistic simulations can be employed for the construction of an “in vitro—in vivo—ex vivo—in cyto—in silico” performance‐correlation profile within biomedical material assemblies.The authors declare that they have no conflicts of interest with the contents of this article.


Fetal weight estimation is of key importance in the decision-making process for obstetric planning and management. The literature is inconsistent on the accuracy of measurements with either ultrasound or clinical examination, known as Leopold’s manoeuvres, shortly before term. Maternal BMI is a confounding factor because it is associated with both the fetal weight and the accuracy of fetal weight estimation. The aim of our study was to compare the accuracy of fetal weight estimation performed with ultrasound and with clinical examination with respect to BMI.In this prospective blinded observational study we investigated the accuracy of clinical examination as compared to ultrasound measurement in fetal weight estimation, taking the actual birth weight as the gold standard.In a cohort of all consecutive patients who presented in our department from January 2016 to May 2017 to register for delivery at ≥37 weeks, examination was done by ultrasound and Leopold’s manoeuvres to estimate fetal weight. All examiners (midwives and physicians) had about the same level of professional experience.The primary aim was to compare overall absolute error, overall absolute percent error, absolute percent error > 10% and absolute percent error > 20% for weight estimation by ultrasound and by means of Leopold’s manoeuvres versus the actual birth weight as the given gold standard, namely separately for normal weight and for overweight pregnant women.Five hundred forty-three patients were included in the data analysis. The accuracy of fetal weight estimation was significantly better with ultrasound than with Leopold’s manoeuvres in all absolute error calculations made in overweight pregnant women. For all error calculations performed in normal weight pregnant women, no statistically significant difference was seen in the accuracy of fetal weight estimation between ultrasound and Leopold’s manoeuvres.Data from our prospective blinded observational study show a significantly better accuracy of ultrasound for fetal weight estimation in overweight pregnant women only as compared to Leopold’s manoeuvres with a significant difference in absolute error. We did not observe significantly better accuracy of ultrasound as compared to Leopold’s manoeuvres in normal weight women. Further research is needed to analyse the situation in normal weight women. Accuracy of fetal weight estimation is of key importance in antenatal care, as well as in the planning and management of labour and mode of delivery –9.In order to achieve more accurate prenatal fetal weight estimations and align these with a risk-optimizing mode of delivery, additional tools supporting the standard of use with ultrasound are needed.The main ultrasonic methods used to calculate the weight of a fetus are based on measurement of fetal abdominal circumference (AC) and estimated fetal weight (EFW) using a formula first described by Hadlock et al. , 11, andAntenatal magnetic resonance imaging (MRI)  or soft-Leopold’s manoeuvres have a long-standing tradition in obstetrics and midwifery and were first described by the German gynaecologist Christian Gerhard Leopold 1846–1911) in the journal “Archiv für Gynäkologie” in the 19th century . By plac846–1911 Maternal body mass index (BMI) has been shown to affect the accuracy of EFW . CliniciWe examined whether clinical assessment is an alternative when ultrasound is not available or can serve as a useful supplemental examination using the actual birth weight as the gold standard. The aim of our prospective blinded observational study was to evaluate the accuracy of fetal weight estimation performed with ultrasound and clinical examination, namely separately for normal weight and for overweight pregnant women.In this prospective blinded observational study we investigated the accuracy of clinical Leopold’s manoeuvres as compared to ultrasound measurements in fetal weight estimation, with the actual birth weight as the gold standard.This is a prospective blinded analysis of a cohort of all consecutive women giving birth, including vertex and breech, singleton gestations who presented for labour ≥37 weeks from January 2016 to May 2017 at our department.To avoid selection bias and perform a real live evaluation, we examined all consecutive women registered for delivery and ultimately delivered at ≥37 weeks. No preterm deliveries prior to 37 weeks are done at our department, but are sent antenatally to a secondary referral centre. Therefore, there are no data on preterm deliveries in our data set.Cases of both spontaneous labour and induction of labour were included as well as planned (primary) and unplanned (secondary) caesarean sections  Patient’s history taken by examining midwife; 2.) Cardiotocography (CTG) for 30 min in pregnant women at risk; 3) basic obstetric vaginal and abdominal examination with Leopold’s manoeuvres by midwife and documentation of EFW (blinded to the physician (sonographer)); 4) ultrasound biometric measurements  of the fetus by the physician (one of six consultants or one of two residents) including EFW (blinded to the examining midwife) registered in a nationwide electronic documentary system (PIA/Viewpoint© by LB-Systems©); 5) pre-delivery discussion with the physician regarding possible risks and mode of delivery.Both the midwife and the physician (sonographer) were blinded to the documentation of the weight of prior babies, and pregnant women were asked not to disclose this information to avoid bias.Every Friday, after the last delivery registration appointment of the week, the measurements were released for comparison. If discrepancies were noticed (> 500 g), these pregnant women were asked to return for re-counselling. Decisions were then based on the ultrasound measurements and their interpretation by a consultant.Calculation by the ultrasound machine and the PIA/Viewpoint© system is based on Hadlock’s formula  includinFetal weight estimation by midwives using Leopold’s manoeuvres is provided as a point estimate rounded off to the nearest 100 g by the examining midwife.All examiners, 13 midwives, six consultants and two residents had a level of professional experience of at least 3 years, as both residents were in their fourth and last year of residency. The range of experience among midwives was 5 years to up to 34 years (mean 16.6), among consultants and residents between four and 34 years (mean 11.8).As previously mentioned, we did not change the pre-existing routine examination, and the midwives already performed Leopold’s manoeuvres as a non-invasive examination for fetal weight estimation before we started our study. The institutional review board (IRB) decision was obtained from the Tauernkliniken GmbH IRB before recruitment for the full trial began in December 2015 (Ref.nr. IRB TK 01_10/2015). All women gave verbal informed consent to participate, which was recorded in the patient’s records.Maternal demographics as well as pregnancy and neonatal outcome information were extracted from electronic medical records (PIA/Viewpoint© by LB-Systems©).In order to extrapolate EFW (Leopold and US) from the examination on the date of birth registration to the actual date of birth, we used the complementary percentile curve for the Austrian population (separately available for girls and boys) .2 and ≥ 25 kg/m2.BMI was evaluated for its impact on clinical estimation of fetal weight. Maternal BMI was calculated from height (self-reported) and weight (measured) at the time of admission and was divided into sub-categories of < 25 kg/mGestational age at registration for delivery was evaluated in intervals of 37 to 39 6/7 weeks, 40 to 40 6/7 weeks, and ≥ 41 weeks.The outcome was to compare overall absolute error, overall absolute percent error, absolute percent error > 10% and absolute percent error > 20% for weight estimation by ultrasound and by Leopold’s manoeuvres versus the actual birth weight as the given gold standard. The estimations and extrapolations were performed according to validated methods to the best of our knowledge. The median time between estimation and birth is shown in Table Baseline characteristics of the study cohort were reported using descriptive statistics.2), parity, mode of delivery , induction of labour and maternal risk factors  for univariate descriptive analysis (“patient characteristics”). Absolute errors  in the estimates were calculated, reporting the mean and SD for the Leopold and the US estimates. It seemed to be practice-relevant to report the proportion of cases with an absolute error ≥ 500 g [We calculated the mean and standard deviation (SD) of maternal age (years), duration of pregnancy (weeks + 6/7 days), fetal weight at birth (grams), body mass index (BMI)  and ≥ 25 kg/m2 (overweight).In order to investigate the effects of BMI on estimate errors, we performed a descriptive analysis as described above, namely separately for the two groups (using two sample tests instead of paired tests). We stratified the results for BMI for < 25 kg/mNormality test was applied first by visual inspection of the respective histograms and then formally by applying the Shapiro-Wilk Test.All statistical analyses were performed using Stata/SE 13.1, Special Edition .A total of 547 pregnant women were eligible to be included, four pregnant women had to be excluded as they gave birth at a different department after registration at our department. Therefore, 543 pregnant women were included in the data analysis. Of the pregnant women in our cohort 5.3% had gestational diabetes. Due to mandatory gestational diabetes screening during pregnancy in Austria and a close follow-up after registration for delivery at our department, which may represent a situation different from that in other countries, we are able to state that these 5.3% pregnant women with gestational diabetes in our cohort were exactly monitored with blood sugar testing. Due to normal results in all 29 patients, who had either diet or insulin, the pregnancies with gestational diabetes in our cohort were comparable to normal pregnancies.Patient characteristics can be found in Table Fetal weight estimation: ultrasound versus Leopold’s manoeuvres.No statistically significant difference was seen in the accuracy of fetal weight estimation performed with Leopold’s manoeuvres versus ultrasound in any absolute error calculations of normal weight women giving birth. This can be seen from Table A statistically significant difference in the accuracy of fetal weight estimation was observed in favour of ultrasound in all absolute error calculations performed in overweight women giving birth. This can be seen from Table A statistically significant difference in the accuracy of fetal weight estimation was observed in favour of ultrasound in all absolute error calculations performed in all women giving birth. This can be seen from Table Density of distribution of estimated fetal weight as compared to actual birthweight established by ultrasound versus palpation is shown in Fig. Fetal weight estimations of normal weight and overweight women with either Leopold’s manoeuvres or ultrasound displaying absolute error, absolute error > 500 g, absolute percent error, absolute error > 10% and absolute error > 20%, including 95% confidence intervals (± 95% CI) are shown in detail in Fig. In this prospective blinded observational study we found a statistically significant difference in the accuracy of fetal weight estimation in favour of ultrasound in all absolute error calculations performed in overweight women giving birth, however no statistically significant difference in normal weight women giving birth.With regard to the mode of delivery and exact timing in the event that it is necessary to induce labour, the accuracy of fetal weight estimation is of key importance in the obstetrician’s decision-making process shared with the expectant mother and has been a matter of discussion for many years .A deviation of 500 g could have a significant impact on the shared decision-making process, particularly with regard to cut-off levels given in international guidelines , 21.First, our study demonstrates a statistically significant difference in the accuracy of fetal weight estimation in favour of ultrasound in all absolute error calculations made in overweight women giving birth. With regard to an absolute error > 500 g that is clinically relevant for the obstetric decision-making process, a significant difference was evident between the two methods when used in overweight pregnant women.These results are in line with previously published data –24.Second, no statistically significant difference was seen in the accuracy of fetal weight estimation obtained with Leopold’s manoeuvres versus ultrasound in absolute error calculations performed in normal weight women giving birth.The most established way to estimate fetal weight is the ultrasound method, as previously described –12 and mInternational percentile curves for EFW, calculated after studies of fetuses in Anglo-Saxon countries and used to check the week-adapted weight of the unborn fetuses worldwide, may not be the right strategy because they pursue a one-size-fits-all policy in approaching what is too large or too small , 26.Very recently Nicolaides et al.  publisheThe long-standing, mainly midwifery-based tradition of clinical weight estimation by means of Leopold’s manoeuvres is a non-invasive approach to fetal weight estimation that is used when ultrasound is not available , 15.The conclusions published in the literature regarding fetal weight estimation are inconsistent, with some studies favouring ultrasound measurement –34. GoetHigh incongruence of study designs and the difference in approaches regarding time of examination, extrapolation of absolute error in matters of actual birth weight, examiner’s experience etc. might explain the variety of different results obtained.As several studies have shown body mass index (BMI) to affect the accuracy of EFW –19, we dWe found a significant difference between ultrasound and clinical palpation with Leopold’s manoeuvres regarding fetal weight estimation in overweight pregnant women.The difficulty of obstetric ultrasound examinations mostly grows with increasing maternal BMI due to diminished visualization, but its impact on fetal weight estimation is described controversially in the existing literature , 22, 23.Furthermore, we found no significant difference between clinical palpation with Leopold’s manoeuvres and ultrasound for fetal weight estimation in normal weight pregnant women.Our study included women who gave birth within the mean time of 13 days after fetal weight estimation. Some study data and systematic review results show that the most accurate estimates can be expected between four and 7 days before delivery –47. NeveIn this connection we used the most recent Austrian percentile curves for the expected actual birth weight  and compared them with the actual birth weight to validate the measurement results. Several studies previously showed that Hadlock’s formula is the most consistently used for normal clinical cohorts , 49.The strengths of our study are that we present prospective data resulting from a pragmatic assessment of pregnant women as they arrived at our department for delivery, representing a normal life situation. Furthermore, the stratification of normal weight and overweight women regarding the effect of BMI on the accuracy of EFW is the major contribution of our study to the existing literature. In the analysis we included all consecutive women giving birth at our department, thus avoiding a selection bias.A limitation of our study is the borderline significance of errors in the group of normal weight pregnant women, which might become significant for a larger pool of patients.We did not investigate inter-observer variation. The time interval between estimation and delivery represents the real life clinical setting at our department.The data obtained in our prospective blinded observational study show ultrasound to have a significantly better accuracy in fetal weight estimation in overweight pregnant women than Leopold’s manoeuvres. However, no statistically significant difference between the two methods was observed in normal weight pregnant women.The clinical method using Leopold’s manoeuvres might be useful in countries with poor infrastructure and thus poor availability of ultrasound devices.


Evolutionary traps are scenarios in which animals are fooled by rapidly changing conditions into preferring poor‐quality resources over those that better improve survival and reproductive success. The maladaptive attraction of aquatic insects to artificial sources of horizontally polarized light  has become a first model system by which scientists can investigate the behavioral mechanisms that cause traps to occur. We employ this field‐based system to experimentally investigate (a) in which portion(s) of the spectrum are polarizationally water‐imitating reflectors attractive to nocturnal terrestrial and aquatics insects, and (b) which modern lamp types result in greater attraction in this typical kind of nocturnal polarized light pollution. We found that most aquatic taxa exhibited preferences for lamps based upon their color spectra, most having lowest preference for lamps emitting blue and red light. Yet, despite previously established preference for higher degrees of polarization of reflected light, most aquatic insect families were attracted to traps based upon their unpolarized spectrum. Chironomid midges, alone, showed a preference for the color of lamplight in both the horizontally polarized and unpolarized spectra indicating only this family has evolved to use light in this color range as a source of information to guide its nocturnal habitat selection. These results demonstrate that the color of artificial lighting can exacerbate or reduce its attractiveness to aquatic insects, but that the strength of attractiveness of nocturnal evolutionary traps, and so their demographic consequences, is primarily driven by unpolarized light pollution. This focuses management attention on limiting broad‐spectrum light pollution, as well as its intentional deployment to attract insects back to natural habitats. Our approach examines variation in riverside captures of seven aquatic and six terrestrial night‐active insect families in simulated water bodies (white and black oil‐filled trays) illuminated by LED, metal‐halide (MH), or HPS lamps. We interpret differentially higher captures among lamp types illuminating oil‐filled horizontal white trays (full‐spectrum reflectors of unpolarized light) as an attraction to a particular spectrum of unpolarized light produced by that lamp and reflected by the tray. Differential attraction to a particular lamp treatment illuminating black trays  is interpreted as evidence of preferential attraction to particular spectra of horizontal polarization. Interactions between tray and lamp types suggest preferential attraction to horizontally polarized light of a spectrum that differs from the preferred spectrum of unpolarized light and 22.1We selected study sites on five different tributaries of the Hudson River in southern New York State, USA. Figure a. Study d, Figures 2/nm) of each light source as a function of wavelength. We selected lamps of wattages that produced similar overall luminosity  among lamp types, though, at different wavelengths  filled with transparent common salad oil to capture insects and assess their relative preference for test surfaces varying in their a) illumination type and b) degree of polarization of reflected light  = 56.3° from the vertical calculated for the refractive index n = 1.5 of vegetable oil. Exposures were standardized for 1/30th of a second at 400 ISO. At the Brewster's angle, surface‐reflected light is perpendicular to the refracted ray penetrating the oil, resulting in the highest possible degree of polarization. Three images were taken of each object with the polarization filter at different angles. Those images were processed via Polarworks© software into images illustrating the degree (d) and angle (α) of polarization at each pixel. We estimated the maximum degree of polarization associated with trays by quantifying the fraction of the d‐patterns composed of black pixels using ImageJ© software. We calculated a window size representing 1/10 of the tray length and height and estimated maximum d as the window giving the maximum value out of 20 nonoverlapping sample locations within the image of each tray nonrandomly focused on portions of the tray with the highest visual estimates of d on the black‐to‐white scale.We measured the reflection–polarization characteristics of oil‐filled trays using imaging polarimetry  on the number of captured individuals within each insect family. Family‐specific analyses serve to illustrate the behavioral preferences of each taxon. For these analyses, we created a standardized abundance metric that would be reflective of the relative fraction of individuals attracted to each treatment and that was insensitive to bias associated with disproportionately high or low captures at one study site relative to others. We adjusted captures of each family associated with each test surface to be a fraction of the total number of captures for that visit at that site, then multiplied each fraction by 100, rounding to the nearest whole individual. We modeled standardized captures using generalized linear models and fit models to negative binomial or Tweedie distributions with a log‐link function. Tweedie is a family of probability distributions, which have positive mass at zero, but are otherwise continuous and include the Poisson distribution which is typical of count data. Negative binomial distributions are also commonly used to model count data. We modeled lamp and tray type as categorical variables, in predicting captures for each family and selected the error distribution model that minimized overdispersion (ĉ).We examined the effect of 1) lamp type and 2) the 33.1dblack = 53%–88%), including values higher than water is generally capable of . Black test surfaces reflected always horizontally polarized light , while white test surfaces reflected mainly vertically polarized light . The small mirror image of light sources reflected by the white trays was horizontally polarized  with maximum d‐values  higher in treatments with nonpolarizing white test surfaces indicating that phototaxis was dominant over polarotaxis. Notably, these aquatic insect groups have been experimentally demonstrated to exhibit preference for water‐reflected light with higher degrees of polarization  in the vicinity. Our results confirm that of previous studies . Indeed, a recent study illustrates the evolution of reduced sensitivity to unpolarized light pollution by urban moths (Altermatt & Ebert, We declare no competing interests.https://doi.org/10.5061/dryad.7m5cv66Data are available from the Dryad Digital Repository:


SNCA, the gene encoding alpha‐synuclein, as well as other genetic alterations are linked to familial Parkinson’s disease cases with high penetrance and hence constitute major genetic risk factors for Parkinson’s disease. However, the preponderance of cases seems sporadic, most likely based on a complex interplay between genetic predispositions, aging processes and environmental influences. Deciphering the impact of these environmental factors and their interactions with the individual genetic background in humans is challenging and often requires large cohorts, complicated study designs, and longitudinal set‐ups. In contrast, rodent models offer an ideal system to study the influence of individual environmental aspects under controlled genetic background and standardized conditions. In this review, we highlight findings from studies examining effects of environmental enrichment mimicking stimulation of the brain by its physical and social surroundings as well as of environmental stressors on brain health in the context of Parkinson’s disease. We discuss possible internal molecular transducers of such environmental cues in Parkinson’s disease rodent models and emphasize their potential in developing novel avenues to much‐needed therapies for this still incurable disease.Accumulation of alpha‐synuclein protein aggregates is the hallmark neuropathologic feature of synucleinopathies such as Parkinson’s disease. Rare point mutations and multiplications in This article is part of the Special Issue “Synuclein” Misfolding and aggregation of α‐syn is a central event in synucleinopathies, and the presence of eosinophilic intracellular inclusions that contain abundant levels of α‐syn reflects the main neuropathological hallmark of these diseases, known as Lewy pathology  are linked to rare familial cases of PD . In addition, many studies suffer from lack of consistency and specificity, possibly due to our highly complex living conditions that include a vast number of environmental variables and stimuli of different quality and quantity. As an alternative strategy, studying the impact of environmental modulation in disease models offers advantages with respect to I. Control and standardization of range and duration of environmental impacts. II. Focus on a specific stimulus on behavioral, structural, molecular, and functional levels. III. Trace the interaction between specific genetic features and environmental exposures.In particular, rodent models are suitable to decipher the impact of environmental factors in PD as toxin‐induced as well as genetic models mimic the disease. Given the central role for α‐syn in PD pathogenesis, α‐syn transgenic models have emerged as valuable models in PD research and are well suited to study the role of environmental factors in disease unfolding. In this work, we highlight findings from studies examining environmental interventions in PD rodent models and point out how they relate to observations in PD patients. Specifically, we will focus on environmental enrichment, as a factor with protective impact on PD, and environmental stress, as a factor proposed to increase the risk of PD, and discuss the possible internal molecular transducers of such environmental influences in PD.Environmental enrichment (EE), a term that has been coined for an enhanced motor and cognitive stimulation, is known to have a broad impact on the organism acting both peripherally and centrally. In the brain, the benefits of such an approach extend to several areas and involve structural and functional modulations that affect brain performance and resilience , including the transcription factors EGR1 and NURR1/NR4A2  and certain brain disorders including occurrence and progression of neurodegenerative diseases (Mejia et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., Combining stress exposure with MPTP or 6‐OHDA insults in toxin‐induced animal models of PD exacerbates neuronal damage, aggravates motor deficits, and triggers neuroinflammatory response in rodents (Pienaar et al., et al., et al., et al., et al., SNCA‐overexpressing mice complemented by aberrant anxiety‐related behavior. These phenotypic manifestations precedes the presence of motor impairments and concurres with modulations of the striatal transcriptome affecting genes linked to neuroinflammation, synaptic signaling, and neurotransmission in SNCA‐overexpressing mice. Importantly, further research that delves into exploring the molecular transducers of the environmental influences will aid shedding light on the intriguing interplay of environment and SNCA related processes.Similar to studies on environmental enrichment, the majority of reports examining the impact of environmental stress in PD models focus on the effects on dopaminergic neurons and dopamine depletion triggered by neurotoxins in toxin‐induced models. Whether environmental stressors have the same impact in genetic models of PD is still poorly investigated. In a study by Wu and colleagues, chronic stress has been shown to trigger motor impairment and degeneration of dopaminergic neurons accompanied by an increase of abnormal α‐syn inclusions and activation of a proinflammatory response in A53T mice (Wu et al., While evidence is converging on the impact of a variety of environmental influences on cause and course of neurodegenerative disorders, there seems to be no single universal environmental factor triggering these disorders. Instead, a combination of environmental elements, genetic predispositions, and aging processes seemingly prime the demise of a specific subset of neurons in these diseases. Identifying the molecular events that govern such demise and that mediate the impact of each of these interacting factors may shed light on potential molecular targets to reverse a physiological state to ultimately prevent, attenuate, or cure these diseases. Because of the dynamic nature of the transcriptome and the epigenome in response to environmental stimuli, these regulatory layers may harbor attractive targets for molecular modulation that eventually exerts its effects on functional and phenotypic endpoints. Hence, several research projects have been and further should be geared towards identifying such molecular targets that either mimic or oppose the environmental or disease attributes. Importantly, translating these findings to clinical trials entails conducting animal studies with high relevance to the human conditions as discussed before (Nithianantharajah and Hannan,