Maternal α-casein deficiency extends the lifespan of offspring and programmes their body composition.

Early nutrition has significant effects on physiological outcomes during adult life. We have analysed the effect of maternal α-casein (CSN1S1) deficiency on the physiological fate of dams and their offspring. α-casein deficiency reduces maternal milk protein concentration by more than 50% and attenuates the growth of pups to 27% (p < 0.001) of controls at the point of weaning. This is associated with a permanent reduction in adult body weight (- 31% at 25 weeks). Offspring nursed by α-casein deficient dams showed a significantly increased lifespan (+ 20%, χ2: 10.6; p = 0.001). Liver transcriptome analysis of offspring nursed by α-casein deficient dams at weaning revealed gene expression patterns similar to those found in dwarf mice (reduced expression of somatotropic axis signalling genes, increased expression of xenobiotic metabolism genes). In adult mice, the expression of somatotropic axis genes returned to control levels. This demonstrates that, in contrast to dwarf mice, attenuation of the GH-IGF signalling axis in offspring nursed by α-casein deficient dams is transient, while the changes in body size and lifespan are permanent. Offspring nursed by α-casein deficient dams showed permanent changes in body composition. Absolute and relative adipose tissue weights (p < 0.05), the percentage of body fat (p < 0.001) as well as adipocyte size in epididymal white adipose tissue are all reduced. Serum leptin levels were 25% of those found in control mice (p < 0.001). Liver lipid content and lipid composition were significantly altered in response to postnatal nutrition. This demonstrates the nutrition in early life programmes adult lipid metabolism, body composition and lifespan.

Comparative assessment of Riesling wine fault development by the electronic tongue and a sensory panel.

Wine faults threaten brand recognition and consumer brand loyalty. The objective of this study was to compare the acuteness of e-tongue and human sensory evaluation of wine fault development in Riesling wine over 42 days of storage. Riesling wines uninoculated (control) or inoculated with 104 CFU/mL cultures of Wickerhamomyces anomalus, Acetobacter aceti, Lactobacillus brevis, or Pediococcus parvulus were assessed every 7 days with the e-tongue and a rate-all-that-apply (RATA) sensory panel. After 7 days of storage, the e-tongue detected differences in all four wine spoilage microorganism treatments, compared to control wine, with discrimination indices over 86%. The RATA sensory panel detected significant differences beginning on day 35 of storage, 28 days after the e-tongue detected differences. This study showed that the e-tongue was more sensitive than the human panel as a detection tool, without sensory fatigue. PRACTICAL APPLICATION: This research is useful for winemakers seeking additional instrumental methods in the early detection of wine faults. Given the results of this study, the e-tongue can be a useful tool for detecting early chemical changes in white wines that have undergone microbial spoilage, providing winemakers with time to mitigate faults before they surpass sensory thresholds.

Site specific insertion of a transgene into the murine α-casein (CSN1S1) gene results in the predictable expression of a recombinant protein in milk.

Gene loci of highly expressed genes provide ideal sites for transgene expression. Casein genes are highly expressed in mammals leading to the synthesis of substantial amounts of casein proteins in milk. The α-casein (CSN1S1) gene has assessed as a site of transgene expression in transgenic mice and a mammary gland cell line. A transgene encoding an antibody light chain gene (A1L) was inserted into the α-casein gene using sequential homologous and site-specific recombination. Expression of the inserted transgene is directed by the α-casein promoter, is responsive to lactogenic hormone activation, leads to the synthesis of a chimeric α-casein/A1L transgene mRNA, and secretion of the recombinant A1L protein into milk. Transgene expression is highly consistent in all transgenic lines, but lower than that of the α-casein gene (4%). Recombinant A1L protein accounted for 0.5% and 1.6% of total milk protein in heterozygous and homozygous transgenic mice, respectively. The absence of the α-casein protein in homozygous A1L transgenic mice leads to a reduction of total milk protein and delayed growth of the pups nursed by these mice. Overall, the data demonstrate that the insertion of a transgene into a highly expressed endogenous gene is insufficient to guarantee its abundant expression.

Study protocol: combined N-of-1 trials to assess open-label placebo treatment for antidepressant discontinuation symptoms [FAB-study].

BACKGROUND: Antidepressant discontinuation is associated with a broad range of adverse effects. Debilitating discontinuation symptoms can impede the discontinuation process and contribute to unnecessary long-term use of antidepressants. Antidepressant trials reveal large placebo effects, indicating a potential use of open-label placebo (OLP) treatment to facilitate the discontinuation process. We aim to determine the effect of OLP treatment in reducing antidepressant discontinuation symptoms using a series of N-of-1 trials. METHODS: A series of randomized, single-blinded N-of-1 trials will be conducted in 20 patients with fully remitted DSM-V major depressive disorder, experiencing moderate to severe discontinuation symptoms following antidepressant discontinuation. Each N-of-1 trial consists of two cycles, each comprising two-week alternating periods of OLP treatment and of no treatment in a random order, for a total of eight weeks. Our primary outcome will be self-reported discontinuation symptoms rated twice daily via the smartphone application 'StudyU'. Secondary outcomes include expectations about discontinuation symptoms and (depressed) mood. Statistical analyses will be based on a Bayesian multi-level random effects model, reporting posterior estimates of the overall and individual treatment effects. DISCUSSION: Results of this trial will provide insight into the clinical application of OLP in treating antidepressant discontinuation symptoms, potentially offering a new cost-effective therapeutic tool. This trial will also determine the feasibility and applicability of a series of N-of-1 trials in a clinical discontinuation trial. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05051995, first registered September 20, 2021.

Disentangling pharmacological and expectation effects in antidepressant discontinuation among patients with fully remitted major depressive disorder: study protocol of a randomized, open-hidden discontinuation trial.

BACKGROUND: Antidepressants are established as an evidence-based, guideline-recommended treatment for Major Depressive Disorder. Prescriptions have markedly increased in past decades, with a specific surge in maintenance prescribing. Patients often remain on antidepressants longer than clinically necessary. When attempting to stop, many patients experience adverse discontinuation symptoms. Discontinuation symptoms can be debilitating and hinder successful discontinuation. While discontinuation symptoms can result from pharmacological effects, evidence on nocebo-induced side effects of antidepressant use suggests that patients' expectations may also influence occurrence. METHODS: To disentangle pharmacological and expectation effects in antidepressant discontinuation, patients with fully remitted Major Depressive Disorder who fulfill German guideline recommendations to discontinue will either remain on or discontinue their antidepressant. Participants' expectations will be manipulated by varying verbal instructions using an open-hidden paradigm. Within the open trial arms, participants will receive full information about treatment, i.e., high expectation. Within the hidden trial arms, participants will be informed about a 50% chance of discontinuing versus remaining on their antidepressant, i.e., moderate expectation. A total of N = 196 participants will be randomly assigned to either of the four experimental groups: open discontinuation (OD; n = 49), hidden discontinuation (HD; n = 49), open continuation (OC; n = 49), or hidden continuation (HC; n = 49). Discontinuation symptom load during the 13-week experimental phase will be our primary outcome measure. Secondary outcome measures include discontinuation symptom load during the subsequent 39-week clinical observation phase, recurrence during the 13-week experimental period, recurrence over the course of the complete 52-week trial evaluated in a time-to-event analysis, and stress, anxiety, and participants' attentional and emotional processing at 13 weeks post-baseline. Blood and saliva samples will be taken as objective markers of antidepressant blood serum level and stress. Optional rsfMRI measurements will be scheduled. DISCUSSION: Until today, no study has explored the interplay of pharmacological effects and patients' expectations during antidepressant discontinuation. Disentangling their effects has important implications for understanding mechanisms underlying adverse discontinuation symptoms. Results can inform strategies to manage discontinuation symptoms and optimize expectations in order to help patients and physicians discontinue antidepressants more safely and effectively. TRIAL REGISTRATION: ClinicalTrials.gov (NCT05191277), January 13, 2022.

Dopaminergic and norepinephrinergic modulation of endogenous event-related potentials: A systematic review and meta-analysis.

Event-related potentials (ERPs) represent the cortical processing of sensory, motor or cognitive functions invoked by particular events or stimuli. A current theory posits that the catecholaminergic neurotransmitters dopamine (DA) and norepinephrine (NE) modulate a number of endogenous ERPs during various cognitive processes. This manuscript aims to evaluate a leading neurotransmitter hypothesis with a systematic overview and meta-analysis of pharmacologic DA and NE manipulation of specific ERPs in healthy subjects during executive function. Specifically, the frontally-distributed P3a, N2, and Ne/ERN (or error-related negativity) are supposedly modulated primarily by DA, whereas the parietally-distributed P3b is thought to be modulated by NE. Based on preceding research, we refer to this distinction between frontally-distributed DA-sensitive and parietally-distributed NE-sensitive ERP components as the Extended Neurobiological Polich (ENP) hypothesis. Our systematic review and meta-analysis indicate that this distinction is too simplistic and many factors interact with DA and NE to influence these specific ERPs. These may include genetic factors, the specific cognitive processes engaged, or elements of study design, i.e. session or sequence effects or data-analysis strategies.

Expectations and Prior Experiences Associated With Adverse Effects of COVID-19 Vaccination.

Importance: Uptake of vaccination against COVID-19 is strongly affected by concerns about adverse effects. Research on nocebo effects suggests that these concerns can amplify symptom burden. Objective: To investigate whether positive and negative expectations prior to COVID-19 vaccination are associated with systemic adverse effects. Design, Setting, and Participants: This prospective cohort study analyzed the association of expected benefits and risks of vaccination, adverse effects at first vaccination, and observed adverse effects in close contacts with severity of systemic adverse effects among adults receiving a second dose of messenger RNA (mRNA)-based vaccines between August 16 and 28, 2021. A total of 7771 individuals receiving the second dose at a state vaccination center in Hamburg, Germany, were invited to participate; of these, 5370 did not respond, 535 provided incomplete information, and 188 were excluded retrospectively. The mobile application m-Path was used for data collection. Main Outcomes and Measures: Primary outcome was a composite severity index of systemic adverse effects in 12 symptom areas measured once daily with an electronic symptom diary over 7 consecutive days. Data were analyzed by mixed-effects multivariable ordered logistic regression adjusted for prevaccine symptom levels and observation times. Results: A total of 10 447 observations from 1678 individuals receiving vaccinations (BNT162b2 [Pfizer BioNTech] in 1297 [77.3%] and mRNA-1273 [Moderna] in 381 [22.7%]) were collected. The participants' median age was 34 (IQR, 27-44) years, and 862 (51.4%) were women. The risk for more severe adverse effects was higher for persons expecting a lower benefit of vaccination (odds ratio [OR] for higher expectations, 0.72 [95% CI, 0.63-0.83]; P < .001), expecting higher adverse effects of vaccination (OR, 1.39 [95% CI, 1.23-1.58]; P < .001), having experienced higher symptom burden at the first vaccination (OR, 1.60 [95% CI, 1.42-1.82]; P < .001), scoring higher on the Somatosensory Amplification Scale (OR, 1.21 [95% CI, 1.06-1.38]; P = .004), and if the vaccine mRNA-1273 was given rather than BNT162b2 (OR, 2.45 [95% CI, 2.01-2.99]; P < .001). No associations were seen for observed experiences. Conclusions and Relevance: In this cohort study, several nocebo effects occurred in the first week after COVID-19 vaccination. The severity of systemic adverse effects was associated not only with vaccine-specific reactogenicity but also more negative prior experiences with adverse effects from the first COVID-19 vaccination, more negative expectations regarding vaccination, and tendency to catastrophize instead of normalize benign bodily sensations. Clinician-patient interactions and public vaccine campaigns may both benefit from these insights by optimizing and contextualizing information provided about COVID-19 vaccines.

Dopaminergic modulation of novelty repetition in Parkinson's disease: A study of P3 event-related brain potentials.

OBJECTIVE: Parkinson's Disease (PD) is a neurodegenerative disease caused by the loss of dopaminergic neurons. Cognitive impairments have been reported using the event-related potential (ERP) technique. Patients show reduced novelty P3 (nP3) amplitudes in oddball experiments, a response to infrequent, surprising stimuli, linked to the orienting response of the brain. The nP3 is thought to depend on dopaminergic neuronal pathways though the effect of dopaminergic medication in PD has not yet been investigated. METHODS: Twenty-two patients with PD were examined "on" and "off" their regular dopaminergic medication in a novelty 3-stimulus-oddball task. Thirty-four healthy controls were also examined over two sessions, but received no medication. P3 amplitudes were compared throughout experimental conditions. RESULTS: All participants showed sizeable novelty difference ERP effects, i.e. ndP3 amplitudes, during both testing sessions. An interaction of diagnosis, medication and testing order was also found, indicating that dopaminergic medication modulated ndP3 in patients with PD across the two testing sessions: We observed enhanced ndP3 amplitudes from PD patients who were off medication on the second testing session. CONCLUSION: Patients with PD 'off' medication showed ERP evidence for repetition-related enhancement of novelty responses. Dopamine depletion in neuronal pathways that are affected by mid-stage PD possibly accounts for this modulation of novelty processing. SIGNIFICANCE: The data in this study potentially suggest that repetition effects on novelty processing in patients with PD are enhanced by dopaminergic depletion.

Decision Tree Learning Algorithm for Classifying Knee Injury Status Using Return-to-Activity Criteria.

Anterior cruciate ligament (ACL) injury rates in female adolescents are increasing. Irrespective of treatment options, approximately 1/3 will suffer secondary ACL injuries following their return to activity (RTA). Despite this, there are no evidence-informed RTA guidelines to aid clinicians in deciding when this should occur. The first step towards these guidelines is to identify relevant and feasible measures to assess the functional status of these patients. The purpose of this study was therefore to evaluate tests frequently used to assess functional capacity following surgery using a Reduced Error Pruning Tree (REPT). Thirty-six healthy and forty-two ACLinjured adolescent females performed a series of functional tasks. Motion analysis along with spatiotemporal measures were used to extract thirty clinically relevant variables. The REPT reduced these variables down to two limb symmetry measures (maximum anterior hop and maximum lateral hop), capable of classifying injury status between the healthy and ACL injured participants with a 69% sensitivity, 78% specificity and kappa statistic of 0.464. We, therefore, conclude that the REPT model was able to evaluate functional capacity as it relates to injury status in adolescent females. We also recommend considering these variables when developing RTA assessments and guidelines.Clinical Relevance- Our results indicate that spatiotemporal measures may differentiate ACL-injured and healthy female adolescents with moderate confidence using a REPT. The identified tests may reasonably be added to the clinical evaluation process when evaluating functional capacity and readiness to return to activity.

The Effect of Transcutaneous Auricular Vagal Nerve Stimulation (taVNS) on P3 Event-Related Potentials during a Bayesian Oddball Task.

Transcutaneous auricular Vagal Nerve Stimulation (taVNS) is a non-invasive brain stimulation technique associated with possible modulation of norepinephrinergic (NE) activity. NE is suspected to contribute to generation of the P3 event-related potential. Recent evidence has produced equivocal evidence whether taVNS influences the P3 in healthy individuals during oddball tasks. We examined the effect of taVNS on P3 amplitudes using a novel visual Bayesian oddball task, which presented 200 sequences of three stimuli. The three consecutive stimuli in each sequence are labelled Draw 1, Draw 2 and Draw 3. In total, 47 Subjects completed this visual Bayesian oddball task under randomised sham and active taVNS stimulation in parallel with an electroencephalographic (EEG) recording. We conducted exploratory analyses of the effect of taVNS on P3 amplitudes separately for Draws. We found typical oddball effects on P3 amplitudes at Draws 1 and 2, but not Draw 3. At Draw 2, the oddball effect was enhanced during active compared to sham taVNS stimulation. These data provide evidence that taVNS influences parietal P3 amplitudes under specific circumstances. Only P3 amplitudes at Draw 2 were affected, which may relate to closure of Bayesian inference after Draw 2. Our findings seemingly support previously reported links between taVNS and the NE system.

Neural correlates of performance monitoring in adult patients with Gilles de la Tourette syndrome: A study of event-related potentials.

OBJECTIVES: Gilles de la Tourette syndrome (GTS) is a neuropsychiatric condition characterized by motor and vocal tics. There is undoubtedly basal ganglia involvement, which are also important for cognitive processes including performance monitoring and interference resolution. We investigated these functions in adult patients with GTS compared to healthy controls (HCs). METHODS: We compared a group of N = 23 adult patients with GTS to N = 27 HC on a flanker task during an EEG recording. Reaction times and error rates were recorded, as well as N2 and Ne/ERN amplitudes. The N2 is an index of interference resolution. The Ne/ERN is a negative fronto-central component, occurring when participants make mistakes. RESULTS: Patients' reaction times were enhanced on incongruent trials compared to HC. Electrophysiological data revealed more frontal components, as well as significantly increased Ne/ERN amplitudes in patients with GTS compared to HC (p = 0.026). CONCLUSIONS: Altered electrophysiological correlates of error processing in adult patients with GTS compared to HC cannot be attributed to differential error probabilities. Potentially, patients recruit compensatory resources from frontal networks to maintain behavioural performance. SIGNIFICANCE: This study gives further insight into cognitive deficits of patients with GTS, and the underlying neural processes of these functions.

The application of retinal fundus camera imaging in dementia: A systematic review.

INTRODUCTION: The ease of imaging the retinal vasculature, and the evolving evidence suggesting this microvascular bed might reflect the cerebral microvasculature, presents an opportunity to investigate cerebrovascular disease and the contribution of microvascular disease to dementia with fundus camera imaging. METHODS: A systematic review and meta-analysis was carried out to assess the measurement of retinal properties in dementia using fundus imaging. RESULTS: Ten studies assessing retinal properties in dementia were included. Quantitative measurement revealed significant yet inconsistent pathologic changes in vessel caliber, tortuosity, and fractal dimension. Retinopathy was more prevalent in dementia. No association of age-related macular degeneration with dementia was reported. DISCUSSION: Inconsistent findings across studies provide tentative support for the application of fundus camera imaging as a means of identifying changes associated with dementia. The potential of fundus image analysis in differentiating between dementia subtypes should be investigated using larger well-characterized samples. Future work should focus on refining and standardizing methods and measurements.

Modulation of retinal image vasculature analysis to extend utility and provide secondary value from optical coherence tomography imaging.

Retinal image analysis is emerging as a key source of biomarkers of chronic systemic conditions affecting the cardiovascular system and brain. The rapid development and increasing diversity of commercial retinal imaging systems present a challenge to image analysis software providers. In addition, clinicians are looking to extract maximum value from the clinical imaging taking place. We describe how existing and well-established retinal vasculature segmentation and measurement software for fundus camera images has been modulated to analyze scanning laser ophthalmoscope retinal images generated by the dual-modality Heidelberg SPECTRALIS(®) instrument, which also features optical coherence tomography.

Parasystole in a mahaim accessory pathway.

Hypertrophic cardiomyopathy's (HCM) association with sudden cardiac death is well recognised. The risk of sudden cardiac death is known to increase when there is a history of unexplained syncope, abnormal blood pressure response during exercise, severe left ventricular hypertrophy or a family history of unexplained death. Implantable Cardioverter Defibrillator (ICD) implantation has been widely used for primary and secondary prevention of sudden cardiac death (SCD) in people with HCM. Subcutaneous ICD (S-ICD) therapy has been developed to overcome some of the problems associated with the transvenous leads used in conventional ICDs. In this article, we report the use of S-ICD in a patient with HCM and multiple risk factors for sudden cardiac death, this device had to be extracted due to recurrent inappropriate shocks caused by over sensing of atrial flutter and failure to treat a VT episode. We are not aware of any reports of inappropriate shocks caused by atrial flutter in people with a S-ICD.

Detection of Salmonella Enteritidis (SE) bacterin in environmental samples from poultry houses using the RapidChek SE immunoassay.

Environmental swabs from pullet houses were tested for the presence of Salmonella Enteritidis (SE) using the RapidChek SE immunoassay test. Of the 1162 samples tested in 2011, 20 samples were positive, but only two samples were confirmed positive for SE by culture. Seventeen positive samples were from pullet houses that had been vaccinated with SE bacterin 2 to 3 days prior to submission to the lab. This study investigated the detection of SE bacterin using the RapidChek SE test system. Swabs were inoculated with different amounts of a commercial SE bacterin. As little as 0.25 ml of the SE bacterin was sufficient to cause positive results with the RapidChek SE test. This finding emphasizes the need to perform bacterial isolation and identification when a positive result occurs using an immunoassay test.

The role of public health inspectors in maintaining housing in northern and rural communities: recommendations to support public health practice.

OBJECTIVE: Although there is much evidence about the effects of particular housing conditions on health, less is known about the practices of public health inspectors (PHIs) in relation to minimizing or eliminating potential housing health risks. The purpose of this qualitative study was to illuminate the practices of PHIs in relation to types of biological and physical housing risks. METHOD: This study used photo vignettes to focus on PHIs' perceptions, options, and resultant interventions with regards to typical housing risks encountered by PHIs in northeastern Ontario. The vignettes represented two general categories of potential housing risks: biological exposures, and physical characteristics of housing. During a semi-structured interview, 34 PHI participants viewed the vignettes, assessed the housing hazard depicted in each, and described the most appropriate intervention. Traditional content analysis methods were used. RESULTS: The assessment of the physical housing hazards was fairly consistent among the PHIs. There seemed to be more variation in their assessment of risk associated with biological factors. Variation in responses was often explained by their different interpretations of the scope of the provincial legislation as well as local public health unit policies and practices. CONCLUSION: This study demonstrated that PHIs' assessment and responses to potential physical housing hazards were influenced by an interplay between variables related to residents, local service partners, organizational culture, and policy. The recommendations for action also range from specific public health unit protocol to broader research and policy advocacy initiatives. Collectively, the recommendations focus on strategies for optimizing the role of PHIs in reducing housing health risks in mid-size urban or rural areas.

Children's perceptions of the Northern Fruit and Vegetable Program in Ontario, Canada.

OBJECTIVE: This study examined students' perceptions of and suggestions for the Northern Fruit and Vegetable Program, a free, school-based fruit and vegetable snack program implemented in elementary schools in 2 regions of northern Ontario, Canada. METHODS: This was a qualitative study involving 18 focus groups with students in 11 elementary schools in the Porcupine region and 7 schools in the Algoma region. One hundred thirty-nine students from grades 5-8 participated in this study. Inductive content analysis was used to identify key themes. RESULTS: Children perceived the Northern Fruit and Vegetable Program to be a valuable program that allowed them to try new fruits and vegetables (FVs). Participants stated they now eat more FVs at home and at school. Participants would like the program offered more frequently and with more variety. CONCLUSIONS AND IMPLICATIONS: Although children identified several areas for program improvement, they generally perceived the program to be positive and valuable in promoting FV consumption.

Late failure of a single-coil transvenous implantable cardioverter-defibrillator lead associated with conductor separation.

Two patients with the same model of single-coil active fix implantable defibrillator lead presented with evidence of lead malfunction, in one case with an abrupt rise in pacing impedance and threshold and in the other with evidence of over-sensing. In both cases, the chest radiograph showed separation of conductors in the defibrillation lead from the main body of the lead.