Development and evaluation of a website with patients experiences of multiple sclerosis: a mixed methods study.

BACKGROUND: A variety of management options (e.g., disease-modifying therapy, lifestyle interventions, rehabilitation) are available for persons with relapsing-remitting multiple sclerosis (MS). Besides coping with the diagnosis, persons with MS have to make complex decisions, e.g., regarding disease-modifying therapies. In addition to factual information, reports of patient experiences may support other patients in their decision-making. Therefore, we developed a website presenting patient experiences illustrated by video, audio and text files. This study aimed to test the acceptability and usability of a website with patient experiences with MS. METHODS: A mixed-methods approach was applied. A total of 69 participants visited the German "Patient Experiences with MS (PExMS)" website and among them, 50 persons with MS and 6 experts completed an online survey. In total, 18 participants took part in telephone interviews or focus groups. Data from the survey were analysed using descriptive statistics. Qualitative data were analysed using thematic analysis. RESULTS: Both quantitative and qualitative responses suggest that the PExMS website was viewed positively by patients and experts. 94% of persons with MS agreed that the information was comprehensible and reliable. 54% felt encouraged to share their health problems with others after having studied the website. 74% claimed to use the website if they had to make a decision regarding their health. Qualitative responses deduced from the website fell into 5 key themes: (1) web design, appearance, and functionality, (2) content, (3) usability, (4) satisfaction, and (5) loyalty. The search for persons of similar age and with comparable experiences was a major driving force to navigate the website. The material on the website was perceived as diverse, covering both positive and negative experiences in daily living with MS. All participants greatly appreciated having access to other people's experiences online and judged the material on the website as particularly helpful in decision-making for disease-modifying therapies. CONCLUSIONS: The findings suggest that the PExMS website might have the potential to be a useful source of audio-visual information for persons with MS. Given the lack of websites available to patients with experiential information, health care professionals may be encouraged to routinely inform patients about this website at regular appointments.

Experiences of persons with multiple sclerosis with rehabilitation-a qualitative interview study.

BACKGROUND: Managing multiple sclerosis (MS) includes different treatment approaches. Rehabilitation is a key strategy in MS for improving functioning, activity and participation. As part of a larger study on overall patient experiences with different treatment approaches, this study aims to give an overview of different patients' experiences and perspectives on inpatient rehabilitation in MS. METHODS: We conducted problem-centered interviews in 50 persons with MS in Germany, of whom most had relapsing-remitting MS. We used the maximum variation sampling method during recruitment. Data were analyzed thematically. RESULTS: As a result of the analysis, three major themes were identified: 1) factors contributing to the decision-making concerning rehabilitation, 2) experience with the rehabilitation setting, 3) benefits of rehabilitation treatments. The treating physicians' attitude had a major impact on the decision to either opt for rehabilitation or not. Setting goals prior to rehabilitation was given a high priority. Exchanging experiences with other persons with MS presented a major benefit from rehabilitation while for some being separated from regular daily life resulted in a more ambiguous attitude ranging from appreciation of escaping daily hassles to substantial behavioral change management. CONCLUSION: Patients reported various experiences in the process of decision-making with regard to rehabilitation. Physicians´ advice, goal setting and the selection of the most suitable rehabilitation clinic were considered most relevant.

Patients experiences with multiple sclerosis disease-modifying therapies in daily life - a qualitative interview study.

BACKGROUND: Besides coping with a disease with many uncertainties, people with relapsing-remitting multiple sclerosis face complex decisions concerning disease-modifying therapies (DMTs). In an interview study, we aimed to assess patients' experiences with DMTs. METHODS: Problem-centred interviews were conducted with 50 people with relapsing-remitting multiple sclerosis in Germany using maximum variation sampling and covering all licensed DMTs. Data were analysed thematically using deductive and inductive categories. RESULTS: 47 of 50 patients had treatment with at least one of the approved DMTs. The main themes were: (1) starting a DMT, (2) switching to another DMT, (3) discontinuing a DMT, and (4) multiple sclerosis without starting a DMT. Different intercorrelated factors influenced the decision-making processes for or against a DMT. Individual experiences with DMTs in daily life contained the effort in administration, success, and failure of DMTs, coping strategies and well-being without DMTs. The decision-making process for or against a DMT and the use of those treatments can be understood as a constant, continually shifting process, complicated by different factors, which change over time. Experiences with DMTs were characterized by attempts to handle uncertainty and to (re)gain control and integrate adaptivity into one's life. CONCLUSIONS: The study provides a rich and nuanced amount of patients' experiences with DMTs. The findings demonstrate the importance for practitioners to look at current life circumstances of patients with multiple sclerosis when recommending a DMT and to promote and enable patients to make informed decisions.

Embedded model discrepancy: A case study of Zika modeling.

Mathematical models of epidemiological systems enable investigation of and predictions about potential disease outbreaks. However, commonly used models are often highly simplified representations of incredibly complex systems. Because of these simplifications, the model output, of, say, new cases of a disease over time or when an epidemic will occur, may be inconsistent with the available data. In this case, we must improve the model, especially if we plan to make decisions based on it that could affect human health and safety, but direct improvements are often beyond our reach. In this work, we explore this problem through a case study of the Zika outbreak in Brazil in 2016. We propose an embedded discrepancy operator-a modification to the model equations that requires modest information about the system and is calibrated by all relevant data. We show that the new enriched model demonstrates greatly increased consistency with real data. Moreover, the method is general enough to easily apply to many other mathematical models in epidemiology.

Data-Driven Corrections of Partial Lotka-Volterra Models.

In many applications of interacting systems, we are only interested in the dynamic behavior of a subset of all possible active species. For example, this is true in combustion models (many transient chemical species are not of interest in a given reaction) and in epidemiological models (only certain subpopulations are consequential). Thus, it is common to use greatly reduced or partial models in which only the interactions among the species of interest are known. In this work, we explore the use of an embedded, sparse, and data-driven discrepancy operator to augment these partial interaction models. Preliminary results show that the model error caused by severe reductions-e.g., elimination of hundreds of terms-can be captured with sparse operators, built with only a small fraction of that number. The operator is embedded within the differential equations of the model, which allows the action of the operator to be interpretable. Moreover, it is constrained by available physical information and calibrated over many scenarios. These qualities of the discrepancy model-interpretability, physical consistency, and robustness to different scenarios-are intended to support reliable predictions under extrapolative conditions.

Effects of L-citrulline supplementation on heat stress physiology, lactation performance and subsequent reproductive performance of sows in summer.

Lactating sows are susceptible to heat stress (HS). Part of the thermoregulatory response to HS is to increase peripheral blood flow, which is mediated in part by the vasodilator, nitric oxide (NO). Therefore, the aim of this experiment was to determine the effect of supplementation of L-citrulline, a NO precursor, on symptoms of HS, lactation performance and subsequent reproductive performance of sows in summer. A total of 221 summer farrowing mixed parity sows were fed either a control diet or supplemented with 1% L-citrulline upon entry to the farrowing house (6 ± 1.8 days for mean ± standard deviation [SD] before farrowing) until weaning (26 ± 1.5 days). The average daily minimum and maximum temperature in the farrowing house was 21.0 ± 1.88 and 29.2 ± 3.82°C (mean ± SD). Rectal temperature, respiration rate, and plasma and urinary nitrite and nitrate (NOx) of sows were measured on the 19th day post-farrowing. Supplemental L-citrulline in the diet did not affect the number of piglets born alive, feed intake of sows, body weight or backfat thickness of sows at weaning, or litter weight gain. L-citrulline tended to reduce piglet pre-weaning mortality rate from 18.6% to 15.6% (p = 0.058). L-citrulline reduced the respiration rate of sows compared to the control diet at 17:00 hr (Time × Diet, p < 0.001); however, rectal temperature was not affected. L-citrulline tended to increase urinary NOx concentrations (127 vs. 224 µM, p = 0.057) but not plasma NOx concentrations. L-citrulline did not affect farrowing rate or number of piglets born alive in the subsequent parity. In conclusion, L-citrulline supplementation reduced respiration rate of lactating sows and reduced piglet pre-weaning mortality rate in summer. Whether the effects were due to a NO-dependent mechanism requires further validation.

Electroencephalographic responses of anaesthetized pigs (Sus scrofa) to tail docking using clippers or cautery iron performed at 2 or 20 days of age.

OBJECTIVE: To compare electroencephalographic (EEG) responses of pigs to tail docking using clippers or cautery iron, performed at 2 or 20 days of age. STUDY DESIGN: Prospective, randomised controlled experimental study. ANIMALS: A total of 40 Large White x Landrace entire male pigs aged 2 (n=20) or 20 (n=20) days were randomly assigned to undergo tail docking using clippers or cautery iron. METHODS: Anaesthesia was induced and maintained with halothane delivered in oxygen. Following instrumentation, end-tidal halothane concentration was stabilised at 1.0±0.05%, and EEG recording commenced. After a 5 minute baseline period, tail docking was performed and recording continued for additional 10 minutes. EEG data were subjected to Fast Fourier transformation, yielding the summary variables median frequency (F50), 95% spectral edge frequency (F95) and total power (PTOT). Variables recorded during the baseline period were compared with those calculated at consecutive 15 second intervals following tail docking. RESULTS: Following tail docking, F50 decreased briefly but significantly in 2-day-olds, whereas 20-day-olds exhibited a sustained increase in F50 (p<0.05). Immediately after tail docking, F50 was overall lower in 2-day-olds than in 20-day-olds (p<0.05). F95 increased after docking in 20-day-olds docked using clippers (p<0.05) but did not change in 20-day-olds docked using cautery iron or in 2-day-olds docked using either method. Overall, F95 was lower in 2-day-olds than in 20-day-olds from 30 to 60 seconds after docking (p<0.05). PTOT decreased after docking in 20-day-olds (p<0.05) but did not change in 2-day-olds. Overall, PTOT was lower in 2- than in 20-day-olds during baseline and after tail docking (p<0.05). CONCLUSIONS AND CLINICAL RELEVANCE: These data suggest that tail docking using clippers is more acutely painful than docking using cautery iron and that docking within the first days of birth may be less acutely painful than docking at a later age.

Use of Cortisol and Adrenal Weight at Pediatric Postmortem.

We studied the relationship between adrenal weight and postmortem cortisol level in cases of infant death, and examined use of these measurements in adrenal insufficiency. We analyzed procurator-fiscal postmortem reports in the West of Scotland over a three year period. Combined adrenal weight was expressed as percentage of total body weight (%TBW). Of 106 cases, median (5th, 95th) %TBW was 0.056 (0.025, 0.23) and median plasma cortisol was 8.4 ug/dl (1.0, 47.1). There was no correlation between %TBW and plasma cortisol (r = 0.09, p = 0.4). The lowest and highest plasma cortisol quartile had medians of 1.9 ug/dl (1.0, 3.4) and 34.3 ug/dl (17.3, 71.5), respectively. Infection was present in 6 cases (23.1%) in the lowest quartile and in 16 cases (61.5%) in the highest quartile (p = 0.01). Our results highlight the difficulty in interpretation of cortisol at postmortem and suggest that adrenal weight measurement alone may be insufficient for diagnosis of adrenal insufficiency.

Worry about recurrence in a multi-ethnic population of breast cancer survivors and their partners.

PURPOSE: The objectives of this study are to describe racial/ethnic differences and clinical/treatment correlates of worry about recurrence and examine modifiable factors in the health care experience to reduce worry among breast cancer survivors, partners, and pairs. METHODS: Women with non-metastatic breast cancer identified by the Detroit and Los Angeles SEER registries between 6/05 and 2/07 were surveyed at 9 months and 4 years. Latina and Black women were oversampled. Partners were surveyed at time 2. Worry about recurrence was regressed on sociodemographics, clinical/treatment, and modifiable factors (e.g., emotional support received by providers) among survivors, partners, and pairs. RESULTS: The final sample included 510 pairs. Partners reported more worry about recurrence than survivors. Compared to Whites, Latinas(os) were more likely to report worry and Blacks were less likely to report worry (all p < 0.05). Partners of survivors who received chemotherapy reported more worry (OR = 2.47 [1.45, 4.22]). Among modifiable factors, survivors and pairs who received more emotional support from providers were less likely to report worry than those survivors and pairs who did not receive such support (OR = 0.56 [0.32, 0.97]) and (OR = 0.45 [0.23,0.85]), respectively. CONCLUSIONS: Early identification of survivors and partners who are reporting considerable worry about recurrence can lead to targeted culturally sensitive interventions to avoid poorer outcomes. Interventions focused on health care providers offering information on risk and emotional support to survivors and partners is warranted.

Familiarity Is Key: Exploring the Effect of Familiarity on the Face-Voice Correlation.

Recent research has examined the extent to which face and voice processing are associated by virtue of the fact that both tap into a common person perception system. However, existing findings do not yet fully clarify the role of familiarity in this association. Given this, two experiments are presented that examine face-voice correlations for unfamiliar stimuli (Experiment 1) and for familiar stimuli (Experiment 2). With care being taken to use tasks that avoid floor and ceiling effects and that use realistic speech-based voice clips, the results suggested a significant positive but small-sized correlation between face and voice processing when recognizing unfamiliar individuals. In contrast, the correlation when matching familiar individuals was significant and positive, but much larger. The results supported the existing literature suggesting that face and voice processing are aligned as constituents of an overarching person perception system. However, the difference in magnitude of their association here reinforced the view that familiar and unfamiliar stimuli are processed in different ways. This likely reflects the importance of a pre-existing mental representation and cross-talk within the neural architectures when processing familiar faces and voices, and yet the reliance on more superficial stimulus-based and modality-specific analysis when processing unfamiliar faces and voices.

FeoA and FeoC are essential components of the Vibrio cholerae ferrous iron uptake system, and FeoC interacts with FeoB.

The ferrous iron transport system Feo is widely distributed among bacterial species, yet its physical structure and mechanism of iron transport are poorly understood. In Vibrio cholerae, the feo operon consists of three genes, feoABC. feoB encodes an 83-kDa protein with an amino-terminal GTPase domain and a carboxy-terminal domain predicted to be embedded in the inner membrane. While FeoB is believed to form the pore for iron transport, the roles of FeoA and FeoC are unknown. In this work, we show that FeoA and FeoC, as well as the more highly conserved FeoB, are all required for iron acquisition by V. cholerae Feo. An in-frame deletion of feoA, feoB, or feoC eliminated iron acquisition. The loss of transport activity in the feoA and feoC mutants was not due to reduced transcription of the feo operon, suggesting that these two small proteins are required for activity of the transporter. feoC was found to encode a protein that interacts with the cytoplasmic domain of FeoB, as determined using the BACTH bacterial two-hybrid system. Two conserved amino acids in FeoC were found to be necessary for the interaction with FeoB in the two-hybrid assay, and when either of these amino acids was mutated in the context of the entire feo operon, iron acquisition via Feo was reduced. No interaction of FeoA with FeoB or FeoC was detected in the BACTH two-hybrid assay.

Associations between Surface and Rectal Temperature Profiles of Low-Birth-Weight Piglets.

The use of infrared cameras to record surface temperature has shown some promise in older pigs, but neonatal piglets are metabolically less mature and experience rapid temperature changes during their first 24 h. The present experiment aimed to compare rectal temperature to surface temperature at the base of the ear, measured using an infrared camera, for piglets of different birth weights. During farrowing, 48 multiparous sows were monitored, and rectal and surface temperatures were recorded for their lower-birth-weight (≤1.2 kg) piglets within 3 min of birth and at 0.25, 0.50, 0.75, 1, 1.25, 1.50, 2, 3, 4, and 24 h. Piglet birth weights were assigned to one of three categories (BWC): BWC1 (≤0.80 kg), BWC2 (0.81 to 1.10 kg), or BWC3 (1.11 to 1.20 kg). Piglet rectal temperatures at 1.25 h after birth were assigned to one of three categories: RC1 (≤32.0 °C), RC2 (32.1 to 35.0 °C), or RC3 (≥35.1 °C). Surface temperatures showed a similar recovery pattern to rectal temperatures in the first 24 h across all piglet birth weights, although large and variable differences seen in the current study militate against surface temperature being an appropriate replacement for neonatal rectal temperature for use in production.

IL-1ß turnover by the UBE2L3 ubiquitin conjugating enzyme and HECT E3 ligases limits inflammation.

The cytokine interleukin-1ß (IL-1ß) has pivotal roles in antimicrobial immunity, but also incites inflammatory disease. Bioactive IL-1ß is released following proteolytic maturation of the pro-IL-1ß precursor by caspase-1. UBE2L3, a ubiquitin conjugating enzyme, promotes pro-IL-1ß ubiquitylation and proteasomal disposal. However, actions of UBE2L3 in vivo and its ubiquitin ligase partners in this process are unknown. Here we report that deletion of Ube2l3 in mice reduces pro-IL-1ß turnover in macrophages, leading to excessive mature IL-1ß production, neutrophilic inflammation and disease following inflammasome activation. An unbiased RNAi screen identified TRIP12 and AREL1 E3 ligases of the Homologous to E6 C-terminus (HECT) family in adding destabilising K27-, K29- and K33- poly-ubiquitin chains on pro-IL-1ß. We show that precursor abundance determines mature IL-1ß production, and UBE2L3, TRIP12 and AREL1 limit inflammation by shrinking the cellular pool of pro-IL-1ß. Our study uncovers fundamental processes governing IL-1ß homeostasis and provides molecular insights that could be exploited to mitigate its adverse actions in disease.

CLC anion channel regulatory phosphorylation and conserved signal transduction domains.

The signaling mechanisms that regulate CLC anion channels are poorly understood. Caenorhabditis elegans CLH-3b is a member of the CLC-1/2/Ka/Kb channel subfamily. CLH-3b is activated by meiotic cell-cycle progression and cell swelling. Inhibition is brought about by GCK-3 kinase-mediated phosphorylation of S742 and S747 located on a ∼176 amino acid disordered domain linking CBS1 and CBS2. Much of the inter-CBS linker is dispensable for channel regulation. However, deletion of a 14 amino acid activation domain encompassing S742 and S747 inhibits channel activity to the same extent as GCK-3. The crystal structure of CmCLC demonstrated that CBS2 interfaces extensively with an intracellular loop connecting membrane helices H and I, the C-terminus of helix D, and a short linker connecting helix R to CBS1. Point mutagenesis of this interface identified two highly conserved aromatic amino acid residues located in the H-I loop and the first α-helix (α1) of CBS2. Mutation of either residue to alanine rendered CLH-3b insensitive to GCK-3 inhibition. We suggest that the dephosphorylated activation domain normally interacts with CBS1 and/or CBS2, and that conformational information associated with this interaction is transduced through a conserved signal transduction module comprising the H-I loop and CBS2 α1.

A sandPIT for Salmonella to play with efferosomes.

In this issue of Cell Host and Microbe, Hiyoshi et al. show that Salmonella uses a type III secretion system (T3SS-2) to damage the Salmonella-containing vacuole, leading to complement deposition on intracellular bacteria followed by neutrophil efferocytosis that protects intracellular bacteria from the respiratory burst.

ARBO: Arbovirus modeling and uncertainty quantification toolbox.

The ongoing pandemic of COVID-19 has highlighted the importance of mathematical tools to understand and predict outbreaks of severe infectious diseases, including arboviruses such as Zika. To this end, we introduce ARBO, a package for simulation and analysis of arbovirus nonlinear dynamics. The implementation follows a minimalist style, and is intuitive and extensible to many settings of vector-borne disease outbreaks. This paper outlines the main tools that compose ARBO, discusses how recent research works about the Brazilian Zika outbreak have explored the package's capabilities, and describes its potential impact for future works on mathematical epidemiology.

Increased feeding frequency prior to farrowing: effects on sow performance.

Reducing the interval between the consumption of the last meal and the start of farrowing is suggested to increase the energy available to sows during farrowing, potentially reducing the farrowing duration and easing piglet births. The present study aimed to examine whether increasing feeding frequency from one to two feeds within standard production hours (0700 to 1500 hours) would produce a difference in farrowing duration and/or stillborn numbers. From entry to farrowing crates (110 ± 1 d gestation) to farrowing (116 ± 1 d gestation), multiparous sows (n = 118) were fed a daily fixed amount of feed either once at 0800 hours or in two meals at 0800 and 1300 hours. Sow weights and backfat depths were recorded on entry and exit from the farrowing crate. Litter size and weight were recorded 24 h after farrowing and on day 21 of lactation. Sows fed twice had a shorter farrowing duration and fewer stillborn piglets than those fed once (2.21 ± 0.56 h vs. 3.25 ± 0.52 h; P = 0.001). The interaction between treatment and farrowing duration showed that sows fed twice have a reduced farrowing duration and had significantly lower stillborn rates than those fed once or those fed twice with longer farrowing durations (P < 0.001). These findings suggest that increasing feeding frequency prior to farrow can reduce the farrowing duration and stillborn numbers in some sows, however, some sows remain with a high stillborn rate regardless of feeding frequency. Piglet average daily gain was greater in once-fed sows, but fewer of these sows remained in the herd at subsequent farrowing. Further, subsequent total born and born alive were higher in twice-fed sows. Feeding sows at a higher frequency can improve farrowing performance in some sows and could increase the longevity of the sow in the herd.

Piglet Morphology: Indicators of Neonatal Viability?

The morphological measures, crown-to-rump length (CR), and abdominal circumference (AC) have been suggested to be as good, if not better, than birth weight for predicting piglet performance. We explored the relationships between CR and AC, and piglet weights at birth and 24 h, to investigate their predictive value for piglet survival. Piglet weight and AC at birth and 24 h, and CR at 24 h were recorded for 373 piglets born to 31 sows. Morphological measures were categorised into two levels for weight and three levels for AC and CR. Further, AC and CR groupings were concatenated to create a new variable (PigProp) to describe the proportionality of piglet morphology. Proportionate piglets had equal CR and AC levels, and disproportionate piglets had contrasting levels. Birth AC was a good predictor of colostrum intake (p < 0.001) when accounting for birth weight, but 24 h weight and PigProp were good indicators of actual colostrum intake (p < 0.001 for both). The significant interaction of colostrum and PigProp showed that within the smaller piglet groups, those who had greater than 200 g of colostrum had higher 24 h weight and survival (p < 0.001 both). As expected, as body weight and colostrum intake increased, so did weight change to d 21 (P = 0.03 and trend at p = 0.1, respectively). A similar pattern was seen with increasing PigProp group (p < 0.001); however, piglets from the disproportionate group 1,3 had the greatest observed weight change (5.15 ± 0.06 kg). Our data show morphological measures may be more predictive of piglet viability in terms of both performance and survival than weight and there may be subgroups that have higher than expected chances of survival.

Combinatorial games with a pass: a dynamical systems approach.

By treating combinatorial games as dynamical systems, we are able to address a longstanding open question in combinatorial game theory, namely, how the introduction of a "pass" move into a game affects its behavior. We consider two well known combinatorial games, 3-pile Nim and 3-row Chomp. In the case of Nim, we observe that the introduction of the pass dramatically alters the game's underlying structure, rendering it considerably more complex, while for Chomp, the pass move is found to have relatively minimal impact. We show how these results can be understood by recasting these games as dynamical systems describable by dynamical recursion relations. From these recursion relations, we are able to identify underlying structural connections between these "games with passes" and a recently introduced class of "generic (perturbed) games." This connection, together with a (non-rigorous) numerical stability analysis, allows one to understand and predict the effect of a pass on a game.

Dietary Modelling to Explore the Impact of Potassium Chloride Replacement for Sodium in Bread for Adults with Chronic Kidney Disease.

Food manufacturers are increasingly substituting potassium chloride (KCl) in food products so as to reduce the sodium chloride content. Bread and bread products are common staple foods in many Western households and are a target for recipe reformulation using KCl. Given that chronic kidney disease (CKD) is a medical condition of global importance that requires dietary potassium restriction in the later stages, we sought to evaluate the impact and safety of varying levels of KCl substitution in bread products. We undertook a secondary analysis of dietary data from the National Nutrition and Physical Activity Survey 2011-2012 for 12,152 participants (154 participants with CKD). The sodium chloride content in bread and bread-based products was substituted with 20%, 30%, and 40% of KCl. The contribution of these alterations in the dietary potassium intake to the total daily potassium intake were then examined. The replacement of sodium in bread with varying amounts of KCl (20%, 30%, and 40%) resulted in one third of people with CKD exceeding the safe limits for dietary potassium consumption (31.8%, 32.6%, and 33%, respectively). KCl substitution in staple foods such as bread and bread products have serious and potentially fatal consequences for people who need to restrict dietary potassium. Improved food labelling is required for consumers to avoid excessive consumption.