Comparison of radiographic scoring systems for assessment of bone healing after tibial plateau leveling osteotomy in dogs.

Introduction: Accurate radiographic assessment of bone healing is vital in determining both clinical treatment and for assessing interventions aimed at the promotion of bone healing. Several scoring systems have been used to evaluate osteotomy changes following tibial plateau leveling osteotomy (TPLO). The goal of this study was to compare the ability of five radiographic scoring systems to identify changes in bone healing following TPLO over time (Aim I), and to evaluate the influence of limb positioning on TPLO osteotomy scoring (Aim II). Materials and methods: Phase I-A randomized, blinded, prospective study was conducted using similarly positioned postoperative TPLO radiographs from seven dogs taken immediately postoperatively, 6-weeks, and 8-weeks postoperatively. Ten reviewers assessed the radiographs, and five different scoring systems were tested for each set including three previously published ones, a Visual Analog Score (VAS), and a subjective 11-point scale. For each system, responses for 6-week postoperative were compared to 8-week postoperative. Scores were judged as correct (=showing an increase in score), incorrect (=decrease in score), or unchanged (=same score). Phase II-An international group of 39 reviewers was asked to score radiographs from three dogs, taken in different positions, using the VAS grading system. Scores were averaged and comparisons were made for each set. Results: Phase I-The VAS system identified the greatest number of sets correctly (76%), with the least unchanged scores (15%), and 9% incorrect scores. Phase II-All three patients had an increase in the average difference between VAS-scores for differently positioned radiographs compared to similarly positioned radiographs. The magnitude of change between different positions far exceeded the magnitude of comparison of the similarly positioned radiographs from the 6- and 8-week time point. Discussion/Conclusion: The VAS system appears to be the most appropriate of the tested systems to identify small changes in bone healing. In addition, the positioning of postoperative TPLO radiographs makes a substantial difference in the healing score that is assigned. Care must be undertaken when performing postoperative radiographs in both the clinical and research setting to ensure accurate assessment of bone healing.

Training generative adversarial networks for optical property mapping using synthetic image data.

We demonstrate the training of a generative adversarial network (GAN) for the prediction of optical property maps (scattering and absorption) using spatial frequency domain imaging (SFDI) image data sets that are generated synthetically with a free open-source 3D modelling and rendering software, Blender. The flexibility of Blender is exploited to simulate 5 models with real-life relevance to clinical SFDI of diseased tissue: flat samples containing a single material, flat samples containing 2 materials, flat samples containing 3 materials, flat samples with spheroidal tumours and cylindrical samples with spheroidal tumours. The last case is particularly relevant as it represents wide-field imaging inside a tubular organ e.g. the gastro-intestinal tract. In all 5 scenarios we show the GAN provides an accurate reconstruction of the optical properties from single SFDI images with a mean normalised error ranging from 1.0-1.2% for absorption and 1.1%-1.2% for scattering, resulting in visually improved contrast for tumour spheroid structures. This compares favourably with the ∼10% absorption error and ∼10% scattering error achieved using GANs on experimental SFDI data. Next, we perform a bi-directional cross-validation of our synthetically-trained GAN, retrained with 90% synthetic and 10% experimental data to encourage domain transfer, with a GAN trained fully on experimental data and observe visually accurate results with an error of 6.3%-10.3% for absorption and 6.6%-11.9% for scattering. Our synthetically trained GAN is therefore highly relevant to real experimental samples but provides the significant added benefits of large training datasets, perfect ground-truths and the ability to test realistic imaging geometries, e.g. inside cylinders, for which no conventional single-shot demodulation algorithms exist. In the future, we expect that the application of techniques such as domain adaptation or training on hybrid real-synthetic datasets will create a powerful tool for fast, accurate production of optical property maps for real clinical imaging systems.

Reducing greenhouse gas emissions through genetic selection in the Australian dairy industry.

This research explores possible options to reduce greenhouse gas (GHG) emissions in the Australian dairy industry by (1) including an environmental component in the national breeding program and (2) estimating the economic and environmental impacts of implementation of the subsequent indexes. A total of 12 possible selection indexes were considered. These indexes were developed to predict changes in gross per-animal methane production (using 3 scenarios depending on availability and efficacy of a direct methane trait breeding value prediction) with 4 different carbon prices, integrating them into an augmentation of the current conventional national selection index. Although some economic response is lost with inclusion of the GHG subindexes in the Balanced Performance Index, options do exist where this loss is marginal and, even in scenarios where all selection pressure is based on the environmental weighting, economic progress is still made in all cases. When including environmental traits within an index, if a relatively low percentage of economic gain or index progression is sacrificed, then approximately 40 to 50% of the maximum possible reductions in emissions may be achieved. This concurrent selection of estimated breeding values that have a correlated favorable response in emissions in addition to direct selection on a residual methane trait allows a high level of methane reduction to be achieved with a realized cost to farmers that is far lower than the economic value placed on carbon. By implementing a GHG subindex in the national breeding program, we can achieve up to a 7.9% decrease in residual methane and 9 times the reduction in gross emissions in 10 yr, compared with the current breeding program, with little to no cost to farmers. By 2050, selection based on one of the more moderate index scenarios at a carbon price of AUD$250/t (AUD$1 = US$0.71), or opportunity cost to farmers of AUD$87.22, will reduce gross emissions by 8.23% and emissions intensity by 21.25%, therefore offering a mitigation strategy that will be effective at reducing emissions with little compromise to profit.

Disease activity and treatment efficacy using patient-level Psoriasis Area and Severity Index scores from tildrakizumab phase 3 clinical trials.

BACKGROUND: It is unclear whether primary efficacy outcomes in plaque psoriasis clinical trials represent residual disease during treatment. OBJECTIVES: To evaluate supplementing dichotomous efficacy with residual disease activity. METHODS: This post hoc analysis used pooled, patient-level data after tildrakizumab 100 mg (N = 616) or placebo (N = 309) treatment from reSURFACE 1/2 (NCT01722331/NCT01729754) phase 3 clinical trials of patients with moderate to severe plaque psoriasis. RESULTS: Median baseline Psoriasis Area and Severity Index (PASI) was 17.9 for patients receiving tildrakizumab 100 mg. At Week 12, median PASI was 2.9, whereas dichotomous PASI 90 response rate was 36.9%, and absolute PASI <5.0, <3.0, and <1.0 were 64.0%, 50.8%, and 23.3%, respectively. At Week 28, median PASI was 1.7, whereas PASI 90 response rate was 51.9%, and absolute PASI <5.0, <3.0, and <1.0 were 75.3%, 62.8%, and 38.0%, respectively. Dermatology Life Quality Index and PASI scores were correlated through Week 28 (r = 0.51, p ≤ .0001). CONCLUSIONS: Disease activity was more reliably estimated by PASI scores than percentage PASI improvement; this may partially explain efficacy disparities between clinical trials and practice. These results suggest supplementing dichotomous PASI improvement with PASI scores and consideration of patient treatment goals could facilitate clinical decisions.

Herd-level versus animal-level variation in methane emission prediction in grazing dairy cattle.

In response to the increased concern over agriculture's contribution to greenhouse gas (GHG) emissions, more detailed assessments of current methane emissions and their variation, within and across individual dairy farms and cattle, are of interest for research and policy development. This assessment will provide insights into possible changes needed to reduce GHG emissions, the nature and direction of these changes, ways to influence farmer behavior and areas to maximize the adoption of emerging mitigation technologies. The objectives of this study were to (1) quantify the variation in enteric fermentation methane emissions within and among seasonal calving dairy farms with the majority of nutritional requirements met through grazed pasture; (2) use this variation to assess the potential of new individual animal emission monitoring technologies and their impact on mitigation policy. We used a large database of cow performance records for milk production and survival from 2 398 herds in New Zealand, and simulation to account for unobserved variation in feed efficiency and methane emissions per unit of feed. Results showed an average of 120 ± 31.4 kg predicted methane (CH4) per cow per year after accounting for replacement costs, ranging 8.9-323 kg CH4/cow per year. Whereas milk production, survival and predicted live weight were reasonably effective at predicting both individual and herd average levels of per cow feed intake, substantial within animal variation in emissions per unit of feed reduced the ability of these variables to predict variation in per animal methane output. Animal-level measurement technologies predicting only feed intake but not emissions per unit of feed are unlikely to be effective for advancing national policy goals of reducing dairy farming enteric methane output. This is because farmers seek to profitably utilize all farm feed resources available, so improvements in feed efficiency will not result in the reduction in feed utilization required to reduce methane emissions. At a herd level, average per cow milk production and live weight could form the basis of assigning a farm-level point of obligation for methane emissions. In conclusion, a comprehensive national database infrastructure that was tightly linked to animal identification and movement systems, and captured live weight data from existing farm-level recording systems, would be required to make this effective. Additional policy and incentivization mechanisms would still be required to encourage farmer uptake of mitigation interventions, such as novel feed supplements or vaccines that reduce methane emissions per unit of feed.

Regenerative and stem cell-based techniques for facial rejuvenation.

This review discusses the most novel ideas and modalities being incorporated into facial rejuvenation. Recent innovative techniques include the use of regenerative stem cell techniques and regeneration supportive modalities such as nano-technology or gene therapies. This review aims to investigate approaches that are less well known and lacking established evidence in order to proactively study these techniques prior to them becoming popularized. These applications and relevant research were reviewed in the context of both surgical and non-surgical modalities in clinical practice. Future directions include the concept of "precision cosmetic medicine" utilizing gene editing and cellular therapies to tailor rejuvenation techniques based on each individual's genetic make-up and therefore needs.

Facial Rejuvenation With Fat Grafting and Fillers.

Facial rejuvenation requires a multi-modality approach to address the sun damage, volume loss, and thinning of skin that occurs with aging. With age, the collagen fibrils that provide strength become fragmented and fibroblasts connections become weak, leading to skin laxity and loss of youthful skin. Fillers can lead to a more youthful appearance by providing volumetric support. Synthetic fillers such as hyaluronic acid products, calcium hydroxyapatite, polylactic acid, and polymethylmethacralate have bio-stimulatory affects, ranging from small effects on fibroblast production to prolonged stimulatory effects on dermal thickness and blood supply. Fat grafting is also an ideal technique for facial rejuvenation because it is readily available, natural, and has regenerative effects. This review describes a new technique of fat grafting for the face called Injectable Tissue Replacement and Regeneration that specifically addresses the different anatomic compartments of the face with volume loss. With this brief review, we aim to evaluate the currents trends of fat grafting and fillers in the management of facial rejuvenation, including the cellular changes that occur with facial aging, the bio-stimulatory effects of fillers, and the anatomic replacement of tissue with fat grafting. >Level of Evidence: 4.

Theoretical and experimental study of peroxy and alkoxy radicals in the NO3-initiated oxidation of isoprene.

The initial stages of the nitrate radical (NO3) initiated oxidation of isoprene, in particular the fate of the peroxy (RO2) and alkoxy (RO) radicals, are examined by an extensive set of quantum chemical and theoretical kinetic calculations. It is shown that the oxidation mechanism is highly complex, and bears similarities to its OH-initiated oxidation mechanism as studied intensively over the last decade. The nascent nitrated RO2 radicals can interconvert by successive O2 addition/elimination reactions, and potentially have access to a wide range of unimolecular reactions with rate coefficients as high as 35 s-1; the contribution of this chemistry could not be ascertained experimentally. The chemistry of the alkoxy radicals derived from these peroxy radicals is affected by the nitrate moiety, and can lead to the formation of nitrated epoxy peroxy radicals in competition with isomerisation and decomposition channels that terminate the organic radical chain by NO2 elimination. The theoretical predictions are implemented in the FZJ-NO3-isoprene mechanism for NO3-initiated atmospheric oxidation of isoprene. The model predictions are compared against peroxy radical (RO2) and methyl vinyl ketone (MVK) measurements in a set of experiments on the isoprene + NO3 reaction system performed in the SAPHIR environmental chamber (IsopNO3 campaign). It is shown that the formation of NO2 from the peroxy radicals can prevent a large fraction of the peroxy radicals from being measured by the laser-induced fluorescence (ROxLIF) technique that relies on a quantitative conversion of peroxy radicals to hydroxyl radicals. Accounting for the relative conversion efficiency of RO2 species in the experiments, the agreement between observations and the theory-based FZJ-NO3-isoprene model predictions improves significantly. In addition, MVK formation in the NO3-initiated oxidation was found to be suppressed by the epoxidation of the unsaturated RO radical intermediates, allowing the model-predicted MVK concentrations to be in good agreement with the measurements. The FZJ-NO3-isoprene mechanism is compared against the MCM v3.3.1 and Wennberg et al. (2018) mechanisms.

Mental Component Score (MCS) from Health-Related Quality of Life Predicts Incidence of Dementia in U.S. Males.

BACKGROUND: The Medical Outcomes Study Questionnaire Short Form 36 health survey (SF-36) measures health-related quality of life (HRQoL) from the individual's point of view and is an indicator of overall health status. OBJECTIVE: To examine whether HRQoL shows differential changes over time prior to dementia onset and investigate whether HRQoL predicts incidence of dementia. DESIGN: Prevention of Alzheimer's Disease (AD) by Vitamin E and Selenium (PREADViSE) trial, which recruited 7,547 non-demented men between 2002 and 2009. A subset of 2,746 PREADViSE participants who completed up to five SF-36 assessments at annual visits was included in the current analysis. SETTING: Secondary data analysis of PREADViSE data. PARTICIPANTS: A subset of 2,746 PREADViSE participants who completed up to five SF-36 assessments at annual visits was included in the current analysis. MEASUREMENTS: Two summary T scores were generated for analysis: physical component score (PCS) and mental component score (MCS), each with a mean of 50 (standard deviation of 10); higher scores are better. Linear mixed models (LMM) were applied to determine if mean component scores varied over time or by eventual dementia status. Cox proportional hazards regression was used to determine if the baseline component scores were associated with dementia incidence, adjusting for baseline age, race, APOE-4 carrier status, sleep apnea, and self-reported memory complaint at baseline. RESULTS: The mean baseline MCS score for participants who later developed dementia (mean± SD: 53.9±9.5) was significantly lower than for those participants who did not develop dementia during the study (mean±SD: 56.4±6.5; p = 0.005). Mean PCS scores at baseline (dementia: 49.3±7.9 vs. non-dementia: 49.8±7.8) were not significantly different (p = 0.5) but LMM analysis showed a significant time effect. For MCS, the indicator for eventual dementia diagnosis was significantly associated with poorer scores after adjusting for baseline age, race, and memory complaint. Adjusted for other baseline risk factors, the Cox model showed that a 10-unit increase in MCS was associated with a 44% decrease in the hazard of a future dementia diagnosis (95% CI: 32%-55%). CONCLUSION: The SF-36 MCS summary score may serve as a predictor for future dementia and could be prognostic in longitudinal dementia research.

A head-to-head comparison of ixekizumab vs. guselkumab in patients with moderate-to-severe plaque psoriasis: 24-week efficacy and safety results from a randomized, double-blinded trial.

BACKGROUND: Significantly more patients with moderate-to-severe plaque psoriasis treated with the interleukin (IL)-17A inhibitor ixekizumab vs. the IL-23p19 inhibitor guselkumab in the IXORA-R head-to-head trial achieved 100% improvement in Psoriasis Area and Severity Index (PASI 100) at week 12. OBJECTIVES: To compare skin and nail clearance and patient-reported outcomes for ixekizumab vs. guselkumab, up to week 24. METHODS: IXORA-R enrolled adults with moderate-to-severe plaque psoriasis, defined as static Physician's Global Assessment ≥ 3, PASI ≥ 12 and involved body surface area ≥ 10%. Statistical comparisons were performed using the Cochran-Mantel-Haenszel test stratified by pooled site. Time-to-first-event comparisons were performed using Kaplan-Meier analysis, and P-values were generated using adjusted log-rank tests stratified by treatment group. Cumulative days at clinical and patient-reported responses were compared by ancova. The trial was registered with ClinicalTrials.gov (NCT03573323). RESULTS: Of the 1027 patients randomly assigned, 90% completed the trial (465 of 520 ixekizumab and 459 of 507 guselkumab). As early as week 2 and through week 16, more patients on ixekizumab achieved PASI 100 (P < 0·01). At week 24, ixekizumab was noninferior to guselkumab (50% vs. 52%, difference -2·3%), with no statistically significant difference in PASI 100 (P = 0·41). More patients receiving ixekizumab showed completely clear nails at week 24 (52% vs. 31%, P = 0·007). The median time to first PASI 50/75/90 and PASI 100 were 2 and 7·5 weeks shorter, respectively, for patients on ixekizumab vs. guselkumab (P < 0·001). Patients on ixekizumab also had a greater cumulative benefit, with more days at PASI 90 and 100, with Dermatology Life Quality Index of 0 or 1, and itch free (P < 0·05). The frequency of serious adverse events was 3% for each group, with no new safety signals. CONCLUSIONS: Ixekizumab was noninferior to guselkumab in complete skin clearance and superior in clearing nails at week 24. Ixekizumab cleared skin more rapidly in patients with moderate-to-severe plaque psoriasis, with a greater cumulative benefit, than guselkumab. Overall, the safety findings were consistent with the known safety profile for ixekizumab.

Genome-Wide Association Analysis of Neonatal White Matter Microstructure.

A better understanding of genetic influences on early white matter development could significantly advance our understanding of neurological and psychiatric conditions characterized by altered integrity of axonal pathways. We conducted a genome-wide association study (GWAS) of diffusion tensor imaging (DTI) phenotypes in 471 neonates. We used a hierarchical functional principal regression model (HFPRM) to perform joint analysis of 44 fiber bundles. HFPRM revealed a latent measure of white matter microstructure that explained approximately 50% of variation in our tractography-based measures and accounted for a large proportion of heritable variation in each individual bundle. An intronic SNP in PSMF1 on chromosome 20 exceeded the conventional GWAS threshold of 5 x 10-8 (p = 4.61 x 10-8). Additional loci nearing genome-wide significance were located near genes with known roles in axon growth and guidance, fasciculation, and myelination.

The Lumbricals Are Not the Workhorse of Digital Extension and Do Not Relax Their Own Antagonist.

That the lumbrical muscles are the workhorse of digital extension and that they can relax their own antagonist have been time-honored principles. However, we believe this dogma is incorrect and an oversimplification. We base our assertion on anatomy, innervation, and the notion that muscle architecture is the most important determinant of muscle function. Wang and colleagues proposed the lumbrical to be a sophisticated tension monitoring device. We elaborate on their well-supported thesis, further proposing that the lumbricals also function as a constant tension spring within the closed loop composed of the digital flexors and the extensor mechanism.

Seed skin grafts for reconstruction of distal limb defects in 15 dogs.

OBJECTIVES: To report the surgical technique of seed skin grafting and clinical application for reconstruction of wounds on the distal limb of client-owned dogs. MATERIALS AND METHODS: Medical records from The Animal Hospital at Murdoch University were retrospectively reviewed for dogs requiring reconstruction using seed grafting for distal limb skin defects between January 2009 and May 2020. RESULTS: Fifteen dogs were included. Grafting was performed on distal limb wounds at or below the carpus or tarsus, following trauma (n = 12) or neoplasia excision (n = 3). Complete epithelialisation with minimal contracture was recorded at a median of 4 weeks (range 3 to 8 weeks) after implantation. Median follow-up was 37 months (range 3 to 55 months) after grafting. Postoperative complications included epidermal inclusion cyst in two dogs. Good functional outcome with acceptable cosmesis despite sparse hair growth was achieved in all cases. CLINICAL SIGNIFICANCE: Seed grafting is a simple technique that can be used reliably to reconstruct wounds on the distal limb in dogs where other reconstructive techniques are not suitable. Complete epithelialisation with sparse hair growth, good long-term functional outcome and minimal complications can be expected.

Carbapenemase screening in an Irish tertiary referral hospital: Best practice, or can we do better?

BACKGROUND: Carbapenems are a family of end line antibiotics with increasing levels of resistance that are a cause for concern. AIM: To ascertain whether the CPE screening programme employed in an acute tertiary hospital is fit for purpose. METHOD: We outlined the current working algorithm employed using a universal screening programme over a 26-month screening period. Rectal swabs are cultured on arrival. Those with suspicious growth are further investigated using NG-Carba 5 lateral flow tests and Vitek 2.0 sensitivity cards. These practices were compared with NHS guidelines. FINDINGS & CONCLUSIONS: In all, 53 true positives were detected from 45 patients since the screening was implemented in early 2018 (46 OXA-48, 6 KPC, 1 NDM). As the rate of screening increased, the number of positive screens decreased over time. There were a lot of similarities between the HSE guidelines and the published NHS CPE toolkit. It was evident that there is no standard practice being employed across all hospitals. Comparing the MUH to national guidelines it appears to be quicker and more effective with universal screening in place at reducing the potential contacts and identifying carriers. Cost analysis indicates that the need to confirm all positive strains in a reference lab is costly, unnecessary and time consuming. There are adequate confirmatory tests available in-house for routine positive screens. It was concluded that infection prevention and control are key to identifying and controlling possible outbreaks in a hospital setting.

Improvements in Clinical Outcomes in Children with Cystic Fibrosis aged Six and 16 years.

Aims Our aim was to assess if outcomes for cystic fibrosis (CF) patients at six & sixteen years of age have improved in the last 17 years looking at FEV1, BMI and death. Methods A retrospective observational study using a prospectively maintained database of CF patients at Cork University Hospital. Results 84 patients were included in the 16-year-old data and 89 patients were included in the six-year-old data. The mean FEV1 and BMI (16 years) for the 2002-2007 group was 72.9±21.0% and 18.9±2.53 respectively, 2008-2013 group was 75.4±27.2% and 19.8±2.7 and for the 2014-2018 group was 95.2±16.0% and 22.9±4.1. The percentage of patients (16 years) with chronic pseudomonas status was 37.9% (11/30) in the 2002-2007 group, 51.6 % (16/31) in the 2008-2013 group and 4.2% (1/24) in the 2014-2018 group. The relationship between FEV1 and FVC with BMI remained significant in multivariate analysis (P <0.001). The mean FEV1 (six years) for the 2002-2007 group was 90.7±16.1%, 2008-2013 group was 99.3±17.9% and for the 2014-2018 group was 100.9±15.8%. Conclusions Improvements in FEV1 and BMI aged six and 16 years are notable as well as a significant decline in the number of patients with chronic pseudomonas.

Altered Brain Structure in Infants with Turner Syndrome.

Turner syndrome (TS) is a genetic disorder affecting approximately 1:2000 live-born females. It results from partial or complete X monosomy and is associated with a range of clinical issues including a unique cognitive profile and increased risk for certain behavioral problems. Structural neuroimaging studies in adolescents, adults, and older children with TS have revealed altered neuroanatomy but are unable to identify when in development differences arise. In addition, older children and adults have often been exposed to years of growth hormone and/or exogenous estrogen therapy with potential implications for neurodevelopment. The study presented here is the first to test whether brain structure is altered in infants with TS. Twenty-six infants with TS received high-resolution structural MRI scans of the brain at 1 year of age and were compared to 47 typically developing female and 39 typically developing male infants. Results indicate that the typical neuroanatomical profile seen in older individuals with TS, characterized by decreased gray matter volumes in premotor, somatosensory, and parietal-occipital cortex, is already present at 1 year of age, suggesting a stable phenotype with origins in the prenatal or early postnatal period.

Baseline patient-reported outcomes from UNITE: an observational, international, multicentre registry to evaluate hidradenitis suppurativa in clinical practice.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic, inflammatory, skin condition associated with many comorbidities and often has a substantial impact on patients' lives. OBJECTIVES: To evaluate symptom burden and health-related quality of life (HRQoL) at baseline in patients with HS in an observational, real-world, clinical setting using several tools including a validated HS-specific instrument. METHODS: This study evaluated HRQoL data from the international UNITE HS disease registry. Administration of patient-reported outcome (PRO) instruments and collection of data were executed per local regulations. All data were assessed using descriptive statistical methods. RESULTS: PRO data from 529 adults and 65 adolescents were evaluated. Most adults (64.5%) and adolescents (73.8%) were classified as Hurley Stage II with substantial disease burden at baseline. HS had a large effect (mean DLQI = 12.6) and moderate effect (mean CDLQI = 6.9) on the lives of adults and adolescents, respectively. Approximately 58% of adults and 41% of adolescents had anxiety scores beyond the normal range; 30% of adults and 16% of adolescents exhibited symptoms of depression. Based on HSSA and HSIA scores, approximately 30% of adults reported a substantial burden of multiple HS clinical symptoms and more than 45% reported a significant emotional impact of HS that adversely affected their intimate relationships. Only 60% of adults were employed and of those, 64% reported at least some degree of impairment while working because of HS. CONCLUSIONS: Based on PROs collected from patients enrolled in the UNITE registry, a real-world, clinical setting, HS has a significant negative impact on the everyday lives of patients affected by this disease.