Finotypic plasticity: Predator-induced plasticity in fin size, darkness and display behaviour in a teleost fish.

Fish fins are remarkable devices of propulsion. Fin morphology is intimately linked to locomotor performance, and hence to behaviours that influence fitness, such as foraging and predator avoidance. This foreshadows a connection between fin morphology and variation in predation risk. Yet, whether prey can adjust fin morphology according to changes in perceived risk within their lifetime (a.k.a. predator-induced plasticity) remains elusive. Here, we quantify the structural size of five focal fins in crucian carp (Carassius carassius) following controlled manipulations to perceived predation risk (presence/absence of pike Esox lucius). We also assess if crucian carp respond to increased predation risk by shifts in dorsal fin colouration, and test for differences in how fish actively use their dorsal fins by quantifying the area of the fin displayed in behavioural trials. We find that crucian carp show phenotypic plasticity with regards to fin size as predator-exposed fish consistently have larger fins. Individuals exposed to perceived predation risk also increased dorsal fin darkness and actively displayed a larger area of the fin to potential predators. Our results thus provide compelling evidence for predator-induced fin enlargement, which should result in enhanced escape swimming performance. Moreover, fin-size plasticity may evolve synergistically with fin colouration and display behaviour, and we suggest that the adaptive value of this synergy is to enhance the silhouette of deep-bodied and hard-to-capture prey to deter gape-limited predators prior to attack. Together, our results provide new perspectives on the role of predation risk in development and evolution of fins.

The impact of prediabetes and diabetes on endothelial function in a large population-based cohort.

BACKGROUND: Diabetes and prediabetes are well-recognized risk factors for cardiovascular disease (CVD) and are marked by vascular endothelial dysfunction (ED). However, there is a scarcity of thorough population-based studies examining ED in individuals with diabetes/prediabetes free from manifest CVD. Here, we examined the association between ED assessed by reactive hyperaemia index (RHI) in the finger and diabetes/prediabetes in a large middle-aged population cohort. METHODS: Within the Malmö Offspring Study, following the exclusion of participants <30 years and participants with prevalent CVD, 1384 participants had complete data on all covariates. The RHI was calculated using pulse amplitude tonometry. ED was defined as RHI < 1.67. Multivariable logistic and linear regression models were conducted to investigate associations between ED and RHI with diabetes and prediabetes. RESULTS: The study population had a mean age of 53.6 ± 7.6 years (53% women). In study participants with manifest diabetes (n = 121) and prediabetes (n = 514), ED was present in 42% and 25% respectively, compared to 23% in those with normal glucometabolic status. In multivariable logistic regression analyses, prevalent diabetes was significantly associated with ED (OR 1.95; 95%CI 1.57-3.39; p = 0.002), as well as with lower RHI (ß-coeff. -0.087; p = 0.002). However, prediabetes showed no association with neither ED nor RHI. CONCLUSION: In a population free from CVD, vascular endothelial dysfunction was primarily associated with manifest diabetes, but not with prediabetes, implying that finger ED may develop when diabetes is established, rather than being an early sign of glucose intolerance. Further research is needed to explore whether addressing glucose intolerance could potentially delay or prevent vascular ED onset.

What is the context?Diabetes and prediabetes are known to increase the risk of cardiovascular disease (CVD) through a condition called vascular endothelial dysfunction (ED). However, there is a lack of comprehensive studies on ED in individuals with diabetes/prediabetes who do not already have CVD. In this study, we investigated the association between ED, assessed using the reactive hyperaemia index (RHI) in a finger, and diabetes/prediabetes in a large group of middle-aged individuals.What is new?We conducted this study within the Malmö Offspring Study, involving 1384 participants who were over 30 years old and did not have pre-existing CVD. The average age of the participants was 53 years, with 53% being women. Among those with diagnosed diabetes (121 individuals) and prediabetes (5141 individuals), 42% and 25% respectively showed signs of ED, compared to 23% in those with normal glucose metabolism. In our analyses, we found that established diabetes was significantly associated with ED, as well as with lower finger RHI values. However, prediabetes did not show any significant association with either ED or RHI.What is the impact? In a healthy population without pre-existing CVD, vascular endothelial dysfunction was predominantly linked to diagnosed diabetes, rather than prediabetes. This suggests that ED may develop once diabetes is established, rather than being an early indicator of glucose intolerance. Further research is necessary to investigate whether addressing glucose intolerance could potentially delay or prevent the onset of vascular ED.

The impact of age on endothelial dysfunction measured by peripheral arterial tonometry in a healthy population-based cohort - the Malmö offspring study.

BACKGROUND/AIMS: The reactive hyperaemia index (RHI) assesses endothelial function, with a proposed cut-off of <1.67 for prevalent endothelial dysfunction (ED). However, uncertainties remain about whether this cut-off is age-dependent and applicable in healthy individuals. We aimed to explore ED in relation to age within a large population-based cohort of young to middle-aged, healthy individuals. METHODS: Within the Malmö Offspring Study, a total of 1812 subjects (50.9% women, mean age 48 ± 11 years) were included. Post-occlusion/pre-occlusion ratio of the pulsatile signal amplitudes in the non-dominant upper arm was used to calculate RHI by EndoPat®. ED was defined as RHI < 1.67. Multivariable regression models were used to explore associations between ED and age. RESULTS: Prevalent ED was found in 534 (29.5%) participants. In subjects aged ≤30 years, ED was present in 47.4% compared to 27.6% in subjects ≥30 years (p < 0.001). In multivariable logistic regression analyses, ED was associated with younger age (p < 0.001), higher BMI (p < 0.001) and current smoking (p < 0.001). No sex differences were observed. CONCLUSION: In a large healthy population, RHI < 1.67, an early marker of endothelial dysfunction, was more prevalent in younger individuals, implying that RHI might not be a suitable measure of endothelial function in individuals under 30 years of age. Our findings suggest that low RHI in young, healthy individuals may not necessarily indicate true ED but rather an artefact of the limited ability of young and healthy arteries to dilate post-occlusion. Therefore, the term "pseudo-ED" may be applicable to young individuals with low RHI values.

What is the context?The endothelium is a thin layer of cells that lines the inside of blood vessels, and its proper function is crucial for the maintenance of vascular health. Endothelial dysfunction (ED) is an early marker of cardiovascular disease and is characterised by impaired dilation of blood vessels, which can lead to reduced blood flow and increased risk of heart attacks and strokes. The reactive hyperaemia index (RHI) is a widely used non-invasive test that measures endothelial function by evaluating the dilation of blood vessels in response to temporary occlusion.What is new?This study aimed to investigate the relationship between age and ED in a large population-based cohort of young to middle-aged healthy individuals. The results showed that prevalent ED was more common in younger individuals, with 47.4% of participants aged ≤30 years having ED, compared to 27.6% in those ≥30 years. The study also found that ED was associated with higher BMI and current smoking, but no sex differences were observed.What is the impact?The findings suggest that the proposed RHI cut-off of <1.67 for prevalent ED may not be applicable to individuals under the age of 30, as young and healthy arteries may have limited ability to dilate post-occlusion, resulting in low RHI values that do not necessarily indicate true ED. Therefore, the term "pseudo-ED" may be more appropriate for young individuals with low RHI values.

Timing and synchrony of migration in a freshwater fish: Consequences for survival.

Animal migration is one of the most spectacular and visible behavioural phenomena in nature with profound implications for a range of ecological and evolutionary processes. Successful migration hinges on the ability to exploit temporary resources (e.g. food) and evade threats (e.g. predators) as they arise, and thus the timing of migration is often regarded as a dominant predictor of individual migratory success. However, with the exception of intensively studied taxa (mainly birds), relatively few studies have investigated inter-individual annual and seasonal variation in migratory timing and performance, or tested predictions on how migration across high and low predation-risk habitats may exert selection on migratory timing. In particular, studies that assess the survival consequences of variation in migratory timing remain rare, which is most likely due to the logistical challenges associated with monitoring survival success and population-level characteristics simultaneously. Here, we address the above-mentioned questions using roach Rutilus rutilus, a fish that migrates from lakes characterised by high predation risk into low-risk streams during winter. Specifically, we used individual-based tracking of roach in two European lake systems over multiple migration periods (9 and 7 years respectively), to obtain highly detailed (year-round scheduling, repeat journeys and the fate of individuals) data on the variability/synchrony of migratory timing in spring and autumn respectively. We report seasonal differences in the variability of migratory timing, with lower variance and higher migration synchrony in spring lake arrival timing as compared to autumn lake departure timing. Furthermore, the timing of autumn migration is more variable across years than the timing of spring migration. Second, we find that later arrival to the lake habitat is positively associated with apparent survival from 1 year to the next, whereas we found no effect of lake departure timing on survival probability. These findings represent rare evidence showing how intraspecific variation in timing in migratory fish differs across years and seasons, and how variation in timing can translate into survival consequences for prey in systems characterised by high predation risk.

Effects of parasitic freshwater mussels on their host fishes: a review.

Freshwater mussels in the order Unionida are highly adapted to parasitize fish for the primary purpose of dispersal. The parasitic larval stage affixes itself to the gills or fins of the host where it becomes encysted in the tissue, eventually excysting to develop into a free-living adult. Research on the parasitic interactions between unionids and their host fishes has garnered attention recently due to the increase in worldwide preservation efforts surrounding this highly endangered and ecologically significant order. With the exception of heavy infestation events, these mussels cause minor effects to their hosts, typically only observable effect in combination with other stressors. Moreover, the range of effect intensities on the host varies greatly with the species involved in the interaction, an effect that may arise from different evolutionary strategies between long- and short-infesting mussels; a distinction not typically made in conservation practices. Lower growth and reduced osmotic potential in infested hosts are commonly observed and correlated with infestation load. These effects are typically also associated with increases in metabolic rate and behaviour indicative of stress. Host fish seem to compensate for this through a combination of rapid wound healing in the parasitized areas and higher ventilation rates. The findings are heavily biased towards Margaritifera margaritifera, a unique mussel not well suited for cross-species generalizations. Furthermore, the small body of molecular and genetic studies should be expanded as many conclusions are drawn from studies on the ultimate effects of glochidiosis rather than proximate studies on the underlying mechanisms.

Postoperative speech impairment and cranial nerve deficits after secondary surgery of posterior fossa tumours in childhood: a prospective European multicentre study.

PURPOSE: Brain tumours constitute 25% of childhood neoplasms, and half of them are in the posterior fossa. Surgery is a fundamental component of therapy, because gross total resection is associated with a higher progression-free survival. Patients with residual tumour, progression of residual tumour or disease recurrence commonly require secondary surgery. We prospectively investigated the risk of postoperative speech impairment (POSI) and cranial nerve dysfunction (CND) following primary and secondary resection for posterior cranial fossa tumours. METHODS: In the Nordic-European study of the cerebellar mutism syndrome, we prospectively included children undergoing posterior fossa tumour resection or open biopsy in one of the 26 participating European centres. Neurological status was assessed preoperatively, and surgical details were noted post-operatively. Patients were followed up 2 weeks, 2 months and 1 year postoperatively. Here, we analyse the risk of postoperative speech impairment (POSI), defined as either mutism or reduced speech, and cranial nerve dysfunction (CND) following secondary, as compared to primary, surgery. RESULTS: We analysed 426 children undergoing primary and 78 undergoing secondary surgery between 2014 and 2020. The incidence of POSI was significantly lower after secondary (12%) compared with primary (28%, p = 0.0084) surgery. In a multivariate analysis adjusting for tumour histology, the odds ratio for developing POSI after secondary surgery was 0.23, compared with primary surgery (95% confidence interval: 0.08-0.65, p = 0.006). The frequency of postoperative CND did not differ significantly after primary vs. secondary surgery (p = 0.21). CONCLUSION: Children have a lower risk of POSI after secondary than after primary surgery for posterior fossa tumours but remain at significant risk of both POSI and CND. The present findings should be taken in account when weighing risks and benefits of secondary surgery for posterior fossa tumours.

SARS-CoV-2 infections amongst personnel providing home care services for older persons in Stockholm, Sweden.

BACKGROUND: In Sweden, home care services is a major external contact for older persons. METHODS: Five home care service companies in Stockholm, Sweden, enrolled 405 employees to a study including serum IgG to SARS-CoV-2 and SARS-CoV-2 virus in throat swabs. RESULTS: 20.1% (81/403) of employees were seropositive, about twice as many as in a simultaneously enrolled reference population (healthcare workers entirely without patient contact, n = 3671; 9.7% seropositivity). 13/379 employees (3.4%) had a current infection (PCR positivity). Amongst these, 5 were also seropositive and 3 were positive with low amounts of virus. High amounts of virus and no antibodies (a characteristic for presymptomatic COVID-19) were present in 5 employees (1.3%). CONCLUSIONS: Personnel providing home services for older persons appear to be a risk group for SARS-CoV-2. Likely presymptomatic employees can be readily identified by screening. Increased protection of employees and of the older persons they serve is warranted.

A clinical model including protein biomarkers predicts radiographic knee osteoarthritis: a prospective study using data from the Osteoarthritis Initiative.

OBJECTIVE: We aimed to provide a model to predict the prospective development of radiographic KOA (rKOA). METHOD: Baseline sera from 333 non-radiographic KOA subjects belonging to OA Initiative (OAI) who developed or not, rKOA during a follow-up period of 96 months were used in this study. The exploratory cohort included 200 subjects, whereas the replication cohort included 133. The levels of inter-alpha trypsin inhibitor heavy chain 1 (ITIH1), complement C3 (C3) and calcyclin (S100A6), identified in previous large proteomic analysis, were analyzed by using sandwich immunoassays on suspension bead arrays. The association of protein levels and clinical covariates with rKOA incidence was assessed by combining logistic regression analysis, Receiver Operating Characteristic (ROC) analysis, Integrated Discrimination Improvement (IDI) analysis and Kaplan-Meier curves. RESULTS: Levels of ITIH1, C3 and S100A6 were significantly associated with the prospective development of rKOA, showing an area under the curve (AUC) of 0.713 (0.624-0.802), 0.708 (0.618-0.799) and 0.654 (0.559-0.749), respectively to predict rKOA in the replication cohort. The inclusion of ITIH1 in the clinical model (age, gender, BMI, previous knee injury and WOMAC pain) improved the predictive capacity of the clinical covariates (AUC = 0.754 [0.670-0.838]) producing the model with the highest AUC (0.786 [0.705-0.867]) and the highest IDI index (9%). High levels of ITIH1 were also associated with an earlier onset of the disease. CONCLUSION: A clinical model including protein biomarkers that predicts incident rKOA has been developed. Among the tested biomarkers, ITIH1 showed potential to improve the capacity to predict rKOA incidence in clinical practice.

Recombinant BRICHOS chaperone domains delivered to mouse brain parenchyma by focused ultrasound and microbubbles are internalized by hippocampal and cortical neurons.

The BRICHOS domain is found in human precursor proteins associated with cancer, dementia (Bri2) and amyloid lung disease (proSP-C). Recombinant human (rh) proSP-C and Bri2 BRICHOS domains delay amyloid-ß peptide (Aß) fibril formation and reduce associated toxicity in vitro and their overexpression reduces Aß neurotoxicity in animal models of Alzheimer's disease. After intravenous administration in wild-type mice, rh Bri2, but not proSP-C, BRICHOS was detected in the brain parenchyma, suggesting that Bri2 BRICHOS selectively bypasses the blood-brain barrier (BBB). Here, our objective was to increase the brain delivery of rh proSP-C (trimer of 18 kDa subunits) and Bri2 BRICHOS (monomer to oligomer of 15 kDa subunits) using focused ultrasound combined with intravenous microbubbles (FUS + MB), which enables targeted and transient opening of the BBB. FUS + MB was targeted to one hemisphere of wild type mice and BBB opening in the hippocampal region was confirmed by magnetic resonance imaging. Two hours after FUS + MB brain histology showed no signs of tissue damage and immunohistochemistry showed abundant delivery to the brain parenchyma in 13 out of 16 cases given 10 mg/kg of proSP-C or Bri2 BRICHOS domains. The Bri2, but not proSP-C BRICHOS domain was detected also in the non-targeted hemisphere. ProSP-C and Bri2 BRICHOS domains were taken up by a subset of neurons in the hippocampus and cortex, and were detected to a minor extent in early endosomes. These results indicate that rh Bri2, but not proSP-C, BRICHOS, can be efficiently delivered into the mouse brain parenchyma and that both BRICHOS domains can be internalized by cell-specific mechanisms.

Personality-dependent inter- and intraspecific foraging competition in the invasive round goby, Neogobius melanostomus.

This study examines the impact of boldness on foraging competition of the highly invasive round goby Neogobius melanostomus Pallas 1815. Individual risk tolerance, or boldness, was measured as the time to resume movement after a simulated predation strike. Fish that resumed movement faster were categorized as "bold," fish that took more time to resume movement were categorized as "shy" and those that fell in between these two categories were determined to have "intermediate" boldness. Competitive impacts of boldness in N. melanostomus were determined in a laboratory foraging experiment in which interspecific (juvenile Atlantic cod Gadus morhua Linnaeus 1758) and intraspecific (intermediate N. melanostomus) individuals were exposed to either bold or shy N. melanostomus competitors. G. morhua consumed fewer prey when competing with bold N. melanostomus than when competing with shy N. melanostomus, whereas intermediately bold N. melanostomus foraging was not affected by competitor boldness. Bold and shy N. melanostomus consumed similar amounts of prey, and the number of interactions between paired fish did not vary depending on the personality of N. melanostomus individuals. Therefore, intraspecific foraging competition was not found to be personality dependent. This study provides evidence that individual differences in boldness can mediate competitive interactions in N. melanostomus; nonetheless, results also show that competition is also governed by other mechanisms that require further study.

Periodontal disease is associated with carotid plaque area: the Malmö Offspring Dental Study (MODS).

BACKGROUND: Periodontal disease is associated with cardiovascular disease (CVD) but it is unknown if periodontal disease severity is associated with asymptomatic carotid plaque. The aim of the current population-based, observational study was to investigate if signs of periodontal disease are associated with the occurrence of carotid plaque and total plaque area (TPA). METHODS: The Malmö Offspring Study (MOS) is a population-based study. MOS participants underwent a thorough cardiovascular phenotyping, including carotid ultrasonography. The Malmö Offspring Dental Study (MODS) invited participants of MOS for dental examination, including periodontal charting. Multivariable regression models were used to analyse the presence of carotid plaque and TPA in relation to periodontal parameters. RESULTS: In all, 831 MODS participants were recruited, out of which 495 belonged to the children generation with mean age of 53 years, 63% had carotid plaque and 38% had moderate or severe periodontal disease. In models adjusted for CVD risk factors, the OR for having carotid plaque in subjects with vs without periodontal disease was 1.75 (95% CI: 1.11-2.78). In a linear model with TPA as dependent and number of periodontal pockets ≥ 4 mm as independent variable, the adjusted beta-coefficient was 0.34 mm2 (95% CI 0.16-0.52). CONCLUSION: Individuals within the highest quartile of periodontal pockets are expected to have 9 mm2 larger TPA compared to those without pockets. Our results suggest that intervention studies addressing periodontal disease could be useful for prevention of CVD.

Incretin hormones, insulin, glucagon and advanced glycation end products in relation to cognitive function in older people with and without diabetes, a population-based study.

AIM: The aim of this observational study was to investigate relationships between physiological levels of glucometabolic biomarkers and cognitive test results in a population-based setting. METHODS: Cross-sectional data were obtained from the Swedish population-based Malmö Diet and Cancer Study Re-examination 2007-2012 comprising 3001 older people (mean age 72 years). Through oral glucose tolerance testing (OGTT), fasting and post-load levels of serum insulin, plasma glucagon, serum glucose-dependent insulinotropic peptide (GIP) and plasma glucagon-like peptide-1 (GLP-1) were measured. Insulin resistance and insulin sensitivity levels were calculated. In 454 participants, advanced glycation end products (AGEs) were estimated through skin autofluorescence. Associations between biomarkers and two cognitive tests, the Mini-Mental State Examination (MMSE) and A Quick Test of Cognitive Speed (AQT) respectively, were explored in multiple regression analyses. RESULTS: Positive associations following adjustments for known prognostic factors were found between MMSE scores and insulin sensitivity (B = 0.822, P = 0.004), 2-h plasma glucagon (B = 0.596, P = 0.026), 2-h serum GIP (B = 0.581, P = 0.040) and 2-h plasma GLP-1 (B = 0.585, P = 0.038), whereas negative associations were found between MMSE scores and insulin resistance (B = -0.734, P = 0.006), fasting plasma GLP-1 (B = -0.544, P = 0.033) and AGEs (B = -1.459, P = 0.030) were found. CONCLUSIONS: Higher levels of insulin sensitivity, GIP and GLP-1 were associated with better cognitive outcomes, but AGEs were associated with worse outcomes, supporting evidence from preclinical studies. Glucagon was linked to better outcomes, which could possibly reflect neuroprotective properties similar to the related biomarker GLP-1 which has similar intracellular properties. Longitudinal and interventional studies are needed to further evaluate neuromodulating effects of these biomarkers. Abstract presented at the European Association for the Study of Diabetes (EASD) 2019, Barcelona, Spain.

Experimental manipulation of perceived predation risk and cortisol generates contrasting trait trajectories in plastic crucian carp.

Most animals constitute potential prey and must respond appropriately to predator-mediated stress in order to survive. Numerous prey also adaptively tailor their response to the prevailing level of risk and stress imposed by their natural enemies, i.e. they adopt an inducible defence strategy. Predator exposure may activate the stress axis, and drive the expression of anti-predator traits that facilitate survival in a high-risk environment (the predation-stress hypothesis). Here, we quantified two key morphological anti-predator traits, body morphology and coloration, in crucian carp reared in the presence or absence of a predator (pike) in addition to experimental manipulation of physiological stress via implants containing either cortisol or a cortisol inhibitor. We found that predator-exposed fish expressed a deeper-bodied phenotype and darker body coloration as compared with non-exposed individuals. Skin analyses revealed that an increase in the amount of melanophores caused the dramatic colour change in predator-exposed fish. Increased melanization is costly, and the darker body coloration may act as an inducible defence against predation, via a conspicuous signal of the morphological defence or by crypsis towards dark environments and a nocturnal lifestyle. By contrast, the phenotype of individuals carrying cortisol implants did not mirror the phenotype of predator-exposed fish but instead exhibited opposite trajectories of trait change: a shallow-bodied morphology with a lighter body coloration as compared with sham-treated fish. The cortisol inhibitor did not influence the phenotype of fish i.e. neither body depth nor body coloration differed between this group and predator-exposed fish with a sham implant. However, our results illuminate a potential link between stress physiology and morphological defence expression.

Substrate-size choice in European eel (Anguilla anguilla) elvers is not altered by piscivore chemical cues.

The European eel Anguilla anguilla Linnaeus 1758 is critically endangered with recruitment estimated at 5-10% of historical levels. Enhancing survival of recruits is pivotal for conservation, and restoration should consider habitat choice of elvers ascending river systems. We experimentally show that newly ascended elvers choose small pebble habitat over finer and larger substrates, regardless of the presence or absence of piscivore chemical cues, indicating no predator-induced change in substrate choice. Enriching habitats with this substrate fraction should enhance eel recruitment as well as biodiversity at large.

A field evaluation of long-term effects of PIT tagging.

Passive integrated transponder (PIT)-tagging is commonly used in behavioural studies of fish, although long-term evaluations of effects from tagging under natural conditions are scarce. We PIT-tagged common bream Abramis brama, European perch Perca fluviatilis, pike Esox lucius and roach Rutilus rutilus, released them in their lakes of origin and recaptured them after 103-3269 days. Overall, tagged fish did not differ in condition from non-tagged fish, except for small R. rutilus that had a lower length-specific body mass in one lake in 1 year. We conclude that PIT-tagging in general has negligible long-term effects on fish condition.

Modelling human pathology of traumatic brain injury in animal models.

Traumatic brain injury (TBI) is caused by a head impact with a force exceeding regular exposure from normal body movement which the brain normally can accommodate. People affected include, but are not restricted to, sport athletes in American football, ice hockey, boxing as well as military personnel. Both single and repetitive exposures may affect the brain acutely and can lead to chronic neurodegenerative changes including chronic traumatic encephalopathy associated with the development of dementia. The changes in the brain following TBI include neuroinflammation, white matter lesions, and axonal damage as well as hyperphosphorylation and aggregation of tau protein. Even though the human brain gross anatomy is different from rodents implicating different energy transfer upon impact, especially rotational forces, animal models of TBI are important tools to investigate the changes that occur upon TBI at molecular and cellular levels. Importantly, such models may help to increase the knowledge of how the pathologies develop, including the spreading of tau pathologies, and how to diagnose the severity of the TBI in the clinic. In addition, animal models are helpful in the development of novel biomarkers and can also be used to test potential disease-modifying compounds in a preclinical setting.

Forewarning of hypotensive events using a Bayesian artificial neural network in neurocritical care.

Traumatically brain injured (TBI) patients are at risk from secondary insults. Arterial hypotension, critically low blood pressure, is one of the most dangerous secondary insults and is related to poor outcome in patients. The overall aim of this study was to get proof of the concept that advanced statistical techniques (machine learning) are methods that are able to provide early warning of impending hypotensive events before they occur during neuro-critical care. A Bayesian artificial neural network (BANN) model predicting episodes of hypotension was developed using data from 104 patients selected from the BrainIT multi-center database. Arterial hypotension events were recorded and defined using the Edinburgh University Secondary Insult Grades (EUSIG) physiological adverse event scoring system. The BANN was trained on a random selection of 50% of the available patients (n = 52) and validated on the remaining cohort. A multi-center prospective pilot study (Phase 1, n = 30) was then conducted with the system running live in the clinical environment, followed by a second validation pilot study (Phase 2, n = 49). From these prospectively collected data, a final evaluation study was done on 69 of these patients with 10 patients excluded from the Phase 2 study because of insufficient or invalid data. Each data collection phase was a prospective non-interventional observational study conducted in a live clinical setting to test the data collection systems and the model performance. No prediction information was available to the clinical teams during a patient's stay in the ICU. The final cohort (n = 69), using a decision threshold of 0.4, and including false positive checks, gave a sensitivity of 39.3% (95% CI 32.9-46.1) and a specificity of 91.5% (95% CI 89.0-93.7). Using a decision threshold of 0.3, and false positive correction, gave a sensitivity of 46.6% (95% CI 40.1-53.2) and specificity of 85.6% (95% CI 82.3-88.8). With a decision threshold of 0.3, > 15 min warning of patient instability can be achieved. We have shown, using advanced machine learning techniques running in a live neuro-critical care environment, that it would be possible to give neurointensive teams early warning of potential hypotensive events before they emerge, allowing closer monitoring and earlier clinical assessment in an attempt to prevent the onset of hypotension. The multi-centre clinical infrastructure developed to support the clinical studies provides a solid base for further collaborative research on data quality, false positive correction and the display of early warning data in a clinical setting.

Targeting Alzheimer's disease with gene and cell therapies.

Alzheimer's disease (AD) causes dementia in both young and old people affecting more than 40 million people worldwide. The two neuropathological hallmarks of the disease, amyloid beta (Aß) plaques and neurofibrillary tangles consisting of protein tau are considered the major contributors to the disease. However, a more complete picture reveals significant neurodegeneration and decreased cell survival, neuroinflammation, changes in protein and energy homeostasis and alterations in lipid and cholesterol metabolism. In addition, gene and cell therapies for severe neurodegenerative disorders have recently improved technically in terms of safety and efficiency and have translated to the clinic showing encouraging results. Here, we review broadly current data within the field for potential targets that could modify AD through gene and cell therapy strategies. We envision that not only Aß will be targeted in a disease-modifying treatment strategy but rather that a combination of treatments, possibly at different intervention times may prove beneficial in curing this devastating disease. These include decreased tau pathology, neuronal growth factors to support neurons and modulation of neuroinflammation for an appropriate immune response. Furthermore, cell based therapies may represent potential strategies in the future.

Autoantibody profiling reveals four protein candidate autoantigens associated with systemic lupus erythematosus.

Objectives In systemic lupus erythematosus (SLE) there are typically many autoantibodies. The disease heterogeneity could be better understood with discovery of phenotype-specific antigens targeted by autoantibodies. We here aimed to identify novel autoantigens potentially related to SLE disease and a major complication, atherosclerosis. Methods Antigen microarrays were used to profile IgG autoantibody reactivity against 77 protein fragments (20-140 amino acids (aa) long, median 89 aa) produced within the Human Protein Atlas project, in serum samples from SLE patients ( n = 107) and age- and sex-matched population-based controls ( n = 107). Common carotid intima-media thickness, plaque occurrence and echogenicity were determined by B-mode ultrasound. Results We determined significant differences between patients and controls in IgG reactivity against four proteins. In patients compared to controls, there was an increase of IgG reactivity against zinc finger protein 688 (ZNF688), early B cell factor 2 (EBF2), crystallin, alpha B (CRYAB) and tumor necrosis factor receptor superfamily member 13C (TNFRSF13C). Of these four antigens, only anti-ZNF688 was associated with carotid atherosclerosis (plaque occurrence) and vulnerable plaques in SLE. There was a weak association between anti-EBF2 and SLE disease activity but no significant associations were determined for other measured IgG reactivity. Conclusions In this discovery screening we here demonstrate new candidate autoantigens with differential reactivity (reflecting autoantibody levels) in SLE patients and in controls and in relation to atherosclerosis in SLE.