Practical lessons learned from real-world implementation of the molecular classification for endometrial carcinoma.

OBJECTIVES: This study aimed to explore the practical organisational aspects and difficulties in the implementation of the molecular classification of endometrial carcinoma (EC), and to demonstrate its potential impact in prognostic risk group classification. METHODS: We conducted a multicentre, retrospective cohort study of 230 patients with EC diagnosed between 2019 and 2022. Sample processing, clinicopathological, treatment and follow-up data were collected. Molecular classification was obtained by p53 and mismatch repair proteins immunohistochemistry, and POLE next-generation sequencing. RESULTS: Implementation was achieved through centralization of molecular analysis. In practice, it was possible to optimise turnaround times of complete integrative reports for hysterectomy specimens to a median time of 18 workdays. If genetic study was started in endometrial biopsies before surgery, 82.0% were available at the time of multidisciplinary tumour board, compared to 8.4% if performed in hysterectomy. ECs were classified as follows: 37.8% no specific molecular profile, 31.7% p53 abnormal, 24.3% mismatch repair deficient, and 6.1% POLE mutant. Integration of these results with traditional clinicopathologic factors led to a change in prognostic risk group in 15 (6.5%) patients, most being initially allocated to high-intermediate (n = 8) and low (n = 5) risk groups. Eight patients changed to a higher risk, and 7 to a lower risk group, whereas 2 remained in the same group. CONCLUSIONS: Centralization of EC molecular classification is a feasible option for countries with limited resources. Optimization of workflows may be achieved by earlier analysis in biopsies and prioritisation of patients whose results imply changes in risk group classification.

Cognitive dysfunction and mortality in multiple sclerosis: Long-term retrospective review.

BACKGROUND: Cognitive dysfunction as a predictor of clinical progression and mortality in multiple sclerosis (MS) is still a matter of debate. OBJECTIVE: The aim of this study was to explore the long-term outcome associated with neuropsychological performance in a cohort of patients with MS. METHODS: A series of 408 MS patients had previously undergone a comprehensive neuropsychological assessment and a contemporaneous neurological evaluation (T1). A retrospective review of the clinical records was conducted 102-192 months after T1. Demographic and clinical data regarding the last clinical appointment with EDSS measurement (T2) were collected and the date of the last clinical contact or death (TS) was recorded. RESULTS: This review revealed that cognitive dysfunction (T1) was associated with higher odds of transitioning from relapsing-remitting course to a progressive disease course (adjusted odds ratio (OR) = 2.29, p = 0.043) and higher hazard of death in the total sample (adjusted hazard ratio (HR) = 3.07, p = 0.006) and the progressive disease course subgroup (adjusted HR = 3.68, p = 0.007), even when adjusting for other covariates. DISCUSSION: The study results demonstrate that cognitive dysfunction in MS is predictive of poorer prognosis and mortality.

Growth and maturity of the lesser-spotted dogfish Scyliorhinus canicula (Linnaeus, 1758) in the southern Portuguese continental coast.

Growth and reproductive parameters were estimated for Scyliorhinus canicula from the south-western Portuguese coast. The sample consisted of 148 specimens with total length ranging from 187 to 580 mm (82 males and 66 females). Maximum ages assigned to males and females were 12 and 13 years, respectively. Linf and k were estimated as 63.6 cm and 0.16 year-1 for males and 63.2 and 0.15 year-1 for females. Length and age at first maturity were estimated as 42.6 cm and 6 years for males and 44.5 cm and 7 years for females.

Comparative virulence of seasonal viruses responsible for lower respiratory tract infections: a southern European multi-centre cohort study of hospital admissions.

OBJECTIVES: Our study aimed to compare the clinical severity of lower respiratory tract infections (LRTI's) caused by Influenza and Respiratory Syncytial Virus (RSV). METHODS: We conducted a retrospective cohort study of LRTI admissions with positive PCR results for Influenza or RSV from 2017 to 2019 in three teaching hospitals in southern Europe. Data on clinical characteristics, viral agents and disease outcome were collected. Nosocomial infection was excluded. Main outcomes were invasive mechanical ventilation and in-hospital death. RESULTS: A total of 984 patients were included. Median age was 75 years. Influenza A was the most frequently identified virus (56.5%), of which 27.1% were subtype H1N1 and 53.0% H3N2. Influenza B was isolated in 22.3% and RSV in 21.0%. There were 10.5% of patients who died during admission and 8.3% submitted to IMV. Influenza A H1N1 was associated with lower age and less co-morbidity, while the opposite was observed for RSV. Influenza A H1N1 was independently associated with both higher risk of death (adjusted odds ratio 2.0 [1.2-3.4] p = 0.008) and IMV (adjusted odds ratio 5.1 [3.0-8.5] p < 0.001). CONCLUSION: Influenza A H1N1 was an independent predictor of mortality and IMV. These findings may have implications on hospital resource planning and vaccination policies.

A Review of Multiple Scale Fibrous and Composite Systems for Heating Applications.

Different types of heating systems have been developed lately, representing a growing interest in both the academic and industrial sectors. Based on the Joule effect, fibrous structures can produce heat once an electrical current is passed, whereby different approaches have been followed. For that purpose, materials with electrical and thermal conductivity have been explored, such as carbon-based nanomaterials, metallic nanostructures, intrinsically conducting polymers, fibers or hybrids. We review the usage of these emerging nanomaterials at the nanoscale and processed up to the macroscale to create heaters. In addition to fibrous systems, the creation of composite systems for electrical and thermal conductivity enhancement has also been highly studied. Different techniques can be used to create thin film heaters or heating textiles, as opposed to the conventional textile technologies. The combination of nanoscale and microscale materials gives the best heating performances, and some applications have already been proven, even though some effort is still needed to reach the industry level.

Biocatalytic Self-Assembly of Tripeptide Gels and Emulsions.

We report on the biocatalytic activation of a self-assembling (unprotected) tripeptide to stabilize oil-in-water emulsions on-demand. This is achieved by the conversion of a phosphorylated precursor into a hydrogelator using alkaline phosphatase (AP) as the trigger. The rate of conversion, controlled by the amount of enzyme used, is shown to play a key role in dictating the morphology of the nanofibrous networks produced. When these amphiphilic tripeptides are used in biphasic mixtures, nanofibers are shown to self-assemble not only at the aqueous/organic interface but also throughout the surrounding buffer, thereby stabilizing the oil-in-water droplet dispersions. The use of enzymatic activation of tripeptide emulsions gives rise to enhanced control of the emulsification process because emulsions can be stabilized on-demand by simply adding AP. In addition, control over the emulsion stabilization can be achieved by taking advantage of the kinetics of dephosphorylation and consequent formation of different stabilizing nanofibrous networks at the interface and/or in the aqueous environment. This approach can be attractive for various cosmetic, food, or biomedical applications because both tunability of the tripeptide emulsion stability and on-demand stabilization of emulsions can be achieved.

Enzymatically activated emulsions stabilised by interfacial nanofibre networks.

We report on-demand formation of emulsions stabilised by interfacial nanoscale networks. These are formed through biocatalytic dephosphorylation and self-assembly of Fmoc(9-fluorenylmethoxycarbonyl)dipeptide amphiphiles in aqueous/organic mixtures. This is achieved by using alkaline phosphatase which transforms surfactant-like phosphorylated precursors into self-assembling aromatic peptide amphiphiles (Fmoc-tyrosine-leucine, Fmoc-YL) that form nanofibrous networks. In biphasic organic/aqueous systems, these networks form preferentially at the interface thus providing a means of emulsion stabilisation. We demonstrate on-demand emulsification by enzyme addition, even after storage of the biphasic mixture for several weeks. Experimental (Fluorescence, FTIR spectroscopy, fluorescence microscopy, electron microscopy, atomic force microscopy) and computational techniques (atomistic molecular dynamics) are used to characterise the interfacial self-assembly process.

Appendectomy may delay Parkinson's disease Onset.

BACKGROUND: Alpha-synuclein (α-Syn) is particularly abundant in the vermiform appendix, which makes this structure an anatomical candidate for the initiation of Parkinson's disease (PD) pathology. We hypothesized that history of appendectomy might affect PD clinical onset. METHODS: A total of 295 PD patients enrolled in a comprehensive observational study were asked about past history of appendectomy. Cox's regression, with a time-dependent covariate, explored the effects of appendectomy on age at PD onset. RESULTS: Thirty-four patients (11.5%) had appendectomy before PD onset. There was no significant effect of appendectomy on age at PD onset for the entire cohort (P = 0.153). However, among patients with late onset (≥55 years), we found evidence that those with past appendectomy had more years of life without PD symptoms than patients without appendectomy (P = 0.040). No association was found for the young-onset group (P = 0.663). CONCLUSIONS: An apparent relationship was observed between appendectomy and PD onset in the late PD cohort.

Cognitive reserve in multiple sclerosis: Protective effects of education.

BACKGROUND: Recent data suggest that cognitive reserve modulates the adverse effects of multiple sclerosis (MS) pathology on cognitive functioning; however, the protective effects of education in MS are still unclear. OBJECTIVE: To explore education as an indicator of cognitive reserve, while controlling for demographic, clinical and genetic features. METHODS: A total of 419 MS patients and 159 healthy comparison (HC) subjects underwent a comprehensive neuropsychological (NP) assessment, and answered the Hospital Anxiety and Depression Scale. Based on the HC data, MS patients' NP scores were adjusted for sex, age and education; and the estimated 5(th) percentile (or 95(th) percentile, when appropriate) was used to identify any deficits. Patients also performed the Mini-Mental State Examination (MMSE); and their human leucocyte antigen HLA-DRB1 and apolipoprotein E (ApoE) genotypes were investigated. RESULTS: Patients with higher education were less likely (p < 0.05) to have cognitive deficits than those with lower education, even when controlling for other covariates. Other significant predictors of cognitive deficit were: age, Expanded Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), and a progressive course. No significant association was found with the HLA-DRB1*15:01 or ApoE ε4 alleles. CONCLUSIONS: These results provide support to the use of education as a proxy of cognitive reserve in MS and stress the need to take into account education when approaching cognition in MS.

Development and assessment of an e-learning course on breast imaging for radiographers: a stratified randomized controlled trial.

BACKGROUND: Mammography is considered the best imaging technique for breast cancer screening, and the radiographer plays an important role in its performance. Therefore, continuing education is critical to improving the performance of these professionals and thus providing better health care services. OBJECTIVE: Our goal was to develop an e-learning course on breast imaging for radiographers, assessing its efficacy, effectiveness, and user satisfaction. METHODS: A stratified randomized controlled trial was performed with radiographers and radiology students who already had mammography training, using pre- and post-knowledge tests, and satisfaction questionnaires. The primary outcome was the improvement in test results (percentage of correct answers), using intention-to-treat and per-protocol analysis. RESULTS: A total of 54 participants were assigned to the intervention (20 students plus 34 radiographers) with 53 controls (19+34). The intervention was completed by 40 participants (11+29), with 4 (2+2) discontinued interventions, and 10 (7+3) lost to follow-up. Differences in the primary outcome were found between intervention and control: 21 versus 4 percentage points (pp), P<.001. Stratified analysis showed effect in radiographers (23 pp vs 4 pp; P=.004) but was unclear in students (18 pp vs 5 pp; P=.098). Nonetheless, differences in students' posttest results were found (88% vs 63%; P=.003), which were absent in pretest (63% vs 63%; P=.106). The per-protocol analysis showed a higher effect (26 pp vs 2 pp; P<.001), both in students (25 pp vs 3 pp; P=.004) and radiographers (27 pp vs 2 pp; P<.001). Overall, 85% were satisfied with the course, and 88% considered it successful. CONCLUSIONS: This e-learning course is effective, especially for radiographers, which highlights the need for continuing education.

Effect of Heavy Metals in Plants of the Genus Brassica.

Several species from the Brassica genus are very important agricultural crops in different parts of the world and are also known to be heavy metal accumulators. There have been a large number of studies regarding the tolerance, uptake and defense mechanism in several of these species, notably Brassica juncea and B. napus, against the stress induced by heavy metals. Numerous studies have also been published about the capacity of these species to be used for phytoremediation purposes but with mixed results. This review will focus on the latest developments in the study of the uptake capacity, oxidative damage and biochemical and physiological tolerance and defense mechanisms to heavy metal toxicity on six economically important species: B. juncea, B. napus, B. oleracea, B. carinata, B. rapa and B. nigra.

Visual vertigo in children- adaptation and validation of the visual vertigo analogue scale to European Portuguese.

BACKGROUND: Visual vertigo occurs after vestibular and non-vestibular pathology and can be present in children and adolescents. It can be assessed by "the Visual Vertigo Analogue Scale" (VVAS), a questionnaire with a Portuguese version for adults. OBJECTIVES: To perform the adaptation to pediatric age and validation of VVAS in European Portuguese. METHODS: This prospective study involved the pediatric adaptation of the Portuguese VVAS, according to recognized guidelines. It was then completed by 30 healthy controls and 18 children with vestibulopathy. Patient caregivers also completed the Dizziness Handicap Inventory - Patient Caregivers (DHI-PC) to further explore the link between questionnaires. Groups were compared for severity of visual vertigo and VVAS test-retest reliability was tested. RESULTS: The VVAS score was significantly higher in vestibular group (p <  0.001). No statistically significant differences were found between VVAS initial and re-test scores (p = 0.33). VVAS severity scores showed a positive correlation with DHI-PC (r = 0.598, p = 0.009). CONCLUSION: The present Pediatric adaptation of VVAS in European Portuguese shows good psychometric properties for the assessment of visual vertigo. A positive correlation with the DHI-PC was showed, establishing the potential use of both questionnaires in the evaluation of vertigo children.

Erasmus Syndrome: An Underrecognized Entity.

We present a case of a 33-year-old male who worked as a plumber and a locksmith. The patient presented with diffuse myalgia and asthenia, skin sclerosis and puffy fingers, Raynaud's phenomenon, exertional dyspnea and erectile dysfunction. The presence of specific autoantibodies enabled the diagnosis of systemic sclerosis. Chest-computed tomography revealed upper lobe consolidation. After extensive evaluation, the multidisciplinary interstitial lung disease team concluded that the patient also had advanced silicosis. After a year, there was significant clinical, radiologic, and functional deterioration of the lung disease. The patient was referred for lung transplant. Silica inhalation is the cause of silicosis but is also implicated in the development of systemic sclerosis (Erasmus syndrome). Although they share a common risk factor, it is rare to find both diseases co-existing. We present this case of a young patient where both diseases presented aggressively in order to raise awareness to this association.

Apresentamos o caso de um homem de 33 anos que trabalhava como canalizador e serralheiro. Apresentava mialgias e astenia, esclerose cutânea e puffy fingers, fenómeno de Raynaud, dispneia de esforço e disfunção erétil. A presença de autoanticorpos específicos permitiu o diagnóstico de esclerose sistémica. A tomografia computadorizada de tórax revelou consolidações dos lobos superiores. Após extensa avaliação, o grupo multidisciplinar de doenças do interstício concluiu que o doente tinha também silicose avançada. Após um ano, houve agravamento clínico, radiológico e funcional significativo da doença pulmonar. O doente foi encaminhado para transplante pulmonar. A inalação de sílica é a causa da silicose, mas também está implicada no desenvolvimento da esclerose sistémica (síndrome de Erasmus). Embora tenham um fator de risco comum, é raro encontrar as duas doenças simultaneamente. Apresentamos o caso de um doente jovem em que ambas as doenças se apresentaram de forma agressiva para alertar sobre esta associação.

The Metabolic and Analytical Changes of Healthy Volunteers upon Intake of Portuguese Extra Virgin Olive Oil: A Comparison Study between Pre- and Post-Intervention.

(1) Background: Extra virgin olive oil (EVOO) is studied mostly for its health benefits in preventing non-communicable chronic diseases, particularly within a Mediterranean dietary pattern. However, few studies have addressed the effect of EVOO in healthy individuals, prior to an established disease. This study aims to evaluate the impact of Northern Portuguese polyphenol-rich EVOO (NPPR-EVOO) consumption on various important clinical parameters in healthy adult volunteers. (2) Methods: This quasi-experimental intervention study assessed the impact of NPPR-EVOO for a period of 100 days. Serum total cholesterol, HbA1c, HDL-c, LDL-c, and CRP, and anthropometric measures-waist and hip perimeters, hand grip strength, and body fat-were assessed and food logs were analyzed. (3) Results: Serum HbA1c (5.12 ± 0.32%; 4.93 ± 0.24, p = 0.000) and LDL-c (96.50 ± 28.57 mg/dL; 87.41 ± 31.38 mg/dL, p = 0.017) significantly decreased following NPPR-EVOO. Also, daily energy significantly increased, but no changes in other dietary parameters, or anthropometry, were seen. Adherence to the Mediterranean diet did not explain the differences found in individuals regarding serum lipid profile and HbA1c, reinforcing the role of EVOO's effect. (4) Conclusions: NPPR-EVOO lowered the serum levels of LDL cholesterol and HbA1c, providing clues on the effect of EVOO-putative health benefits. These results pave the way for a deeper exploration of EVOO as a functional food.

Klotho and lean mass as novel cardiovascular risk factors in hemodialysis patients.

Background: Patients with chronic kidney disease (CKD) present a higher risk of cardiovascular (CV) morbidity and mortality compared with the general population. While there are several well-established traditional CV risk factors, few studies have addressed novel potential risk factors such as α-Klotho, asymmetric dimethylarginine (ADMA) and lean mass. Methods: This was an observational, prospective, single-center, cohort study that included prevalent hemodialysis (online hemodiafiltration) adult patients. By univariate logistic regression models, univariate and multivariate Cox proportional hazards models, and Kaplan-Meier analysis, we evaluated the association between the levels of α-Klotho, ADMA and lean mass, with the risk of peripheral vascular disease (PVD), CV events and all-cause mortality in these patients. Results: A total of 200 HD patients was included. We found that increased levels of log-α-Klotho were significantly associated with decreased odds of both PVD [odds ratio (OR) 0.521, 95% confidence interval (CI) 0.270-0.954, P = .034] and CV events (OR 0.415, 95% CI 0.203-0.790, P = .01), whereas increased levels of log-ADMA were only significantly associated with increased odds of PVD (OR 13.482, 95% CI 5.055-41.606, P < .001). We also found that the levels of log-α-Klotho (HR 0.357, 95% CI 0.140-0.906, P < .05) and lean mass (HR 0.187, 95% CI 0.042-0.829, P < .05), but not log-ADMA, were significantly associated with the risk of all-cause mortality, even after adjusting for possible confounding variables. Conclusions: Novel long-term clinical associations were generated that support α-Klotho and lean mass as novel CV risk factors in hemodialysis patients.

Neoadjuvant Gastric Cancer Treatment and Associated Nutritional Critical Domains for the Optimization of Care Pathways: A Systematic Review.

(1) Background: Gastric cancer patients are known to be at a high risk of malnutrition, sarcopenia, and cachexia, and the latter impairs the patient's nutritional status during their clinical course and also treatment response. A clearer identification of nutrition-related critical points during neoadjuvant treatment for gastric cancer is relevant to managing patient care and predicting clinical outcomes. The aim of this systematic review was to identify and describe nutrition-related critical domains associated with clinical outcomes. (2) Methods: We performed a systematic review (PROSPERO ID:CRD42021266760); (3) Results: This review included 14 studies compiled into three critical domains: patient-related, clinical-related (disease and treatment), and healthcare-related. Body composition changes during neoadjuvant chemotherapy (NAC) accounted for the early termination of chemotherapy and reduced overall survival. Sarcopenia was confirmed to have an independent prognostic value. The role of nutritional interventions during NAC has not been fully explored. (4) Conclusions: Understanding critical domain exposures affecting nutritional status will enable better clinical approaches to optimize care plans. It may also provide an opportunity for the mitigation of poor nutritional status and sarcopenia and their deleterious clinical consequences.

Hierarchical self-assembly of a reflectin-derived peptide.

Reflectins are a family of intrinsically disordered proteins involved in cephalopod camouflage, making them an interesting source for bioinspired optical materials. Understanding reflectin assembly into higher-order structures by standard biophysical methods enables the rational design of new materials, but it is difficult due to their low solubility. To address this challenge, we aim to understand the molecular self-assembly mechanism of reflectin's basic unit-the protopeptide sequence YMDMSGYQ-as a means to understand reflectin's assembly phenomena. Protopeptide self-assembly was triggered by different environmental cues, yielding supramolecular hydrogels, and characterized by experimental and theoretical methods. Protopeptide films were also prepared to assess optical properties. Our results support the hypothesis for the protopeptide aggregation model at an atomistic level, led by hydrophilic and hydrophobic interactions mediated by tyrosine residues. Protopeptide-derived films were optically active, presenting diffuse reflectance in the visible region of the light spectrum. Hence, these results contribute to a better understanding of the protopeptide structural assembly, crucial for the design of peptide- and reflectin-based functional materials.

Comparison of Zinc Oxide Nanoparticle Integration into Non-Woven Fabrics Using Different Functionalisation Methods for Prospective Application as Active Facemasks.

The development of advanced facemasks stands out as a paramount priority in enhancing healthcare preparedness. In this work, different polypropylene non-woven fabrics (NWF) were characterised regarding their structural, physicochemical and comfort-related properties. The selected NWF for the intermediate layer was functionalised with zinc oxide nanoparticles (ZnO NPs) 0.3 and 1.2wt% using three different methods: electrospinning, dip-pad-dry and exhaustion. After the confirmation of ZnO NP content and distribution within the textile fibres by morphological and chemical analysis, the samples were evaluated regarding their antimicrobial properties. The functionalised fabrics obtained via dip-pad-dry unveiled the most promising data, with 0.017 ± 0.013wt% ZnO NPs being mostly located at the fibre's surface and capable of total eradication of Staphylococcus aureus and Escherichia coli colonies within the tested 24 h (ISO 22196 standard), as well as significantly contributing (**** p < 0.0001) to the growth inhibition of the bacteriophage MS2, a surrogate of the SARS-CoV-2 virus (ISO 18184 standard). A three-layered structure was assembled and thermoformed to obtain facemasks combining the previously chosen NWF, and its resulting antimicrobial capacity, filtration efficiency and breathability (NP EN ISO 149) were assessed. The developed three-layered and multiscaled fibrous structures with antimicrobial capacities hold immense potential as active individual protection facemasks.

Development of Smart Clothing to Prevent Pressure Injuries in Bedridden Persons and/or with Severely Impaired Mobility: 4NoPressure Research Protocol.

Pressure injuries (PIs) are a major public health problem and can be used as quality-of-care indicators. An incipient development in the field of medical devices takes the form of Smart Health Textiles, which can possess innovative properties such as thermoregulation, sensing, and antibacterial control. This protocol aims to describe the process for the development of a new type of smart clothing for individuals with reduced mobility and/or who are bedridden in order to prevent PIs. This paper's main purpose is to present the eight phases of the project, each consisting of tasks in specific phases: (i) product and process requirements and specifications; (ii and iii) study of the fibrous structure technology, textiles, and design; (iv and v) investigation of the sensor technology with respect to pressure, temperature, humidity, and bioactive properties; (vi and vii) production layout and adaptations in the manufacturing process; (viii) clinical trial. This project will introduce a new structural system and design for smart clothing to prevent PIs. New materials and architectures will be studied that provide better pressure relief, thermo-physiological control of the cutaneous microclimate, and personalisation of care.

Olfactory dysfunction in multiple sclerosis: association with secondary progression.

OBJECTIVE: The Brief Smell Identification Test (B-SIT) was used to explore odour identification capacities in multiple sclerosis (MS). METHODS: In total, 153 consecutive patients with MS and 165 healthy controls (HC) participated in the study. All participants were asked to answer the B-SIT and the Hospital Anxiety and Depression Scale (HADS). The Expanded Disability Status Scale (EDSS), the Multiple Sclerosis Severity Scale (MSSS), and the Mini-Mental State Examination (MMSE) were used for patients' clinical and cognitive characterization. RESULTS: Patients with MS (11.1%) were more impaired on the B-SIT than HC participants (3%). The frequency of impairment was higher for patients with secondary progressive (SPMS; 11/16, 68.8%) than relapsing-remitting (RRMS; 4/121, 3.3%) or primary progressive (2/16, 12.5%) courses. A threshold score of ≤ 8 on the B-SIT provided a sensitivity of 69% and a specificity of 97% in the identification of SPMS among patients with relapsing onset. The association between SPMS and impaired B-SIT remained statistically significant after adjusting for demographic (i.e. age and education), clinical (i.e. disease duration, EDSS, and MSSS), psychopathological (i.e. HADS anxiety and depression scores), and cognitive (i.e. MMSE) variables. CONCLUSIONS: A brief odour identification measure provided a good discrimination between SPMS and RRMS courses. A systematic assessment of olfactory functions may contribute to the development of clinical markers of SPMS.