Reaction Mechanism Catalyzed by the Dissimilatory Sulfite Reductase - The Role of the Siroheme-[4FeS4] Cofactor.

The present work is another part of our investigation on the pathway of dissimilatory sulfate reduction and covers a theoretical study on the reaction catalyzed by dissimilatory sulfite reductase (dSIR). dSIR is the terminal enzyme involved in this metabolic pathway, which uses the siroheme-[4Fe4S] cofactor for six-electron reduction of sulfite to sulfide. In this study we use a large cluster model containing siroheme-[4Fe4S] cofactor and protein residues involved in the direct interactions with the substrate, to get insight into the most feasible reaction mechanism and to understand the role of each considered active site component. In combination with earlier studies reported in the literature, our results lead to several interesting insights. One of the most important conclusions is that the reaction mechanism consists of three steps of two-electron reduction of sulfur and the probable role of the siroheme-[4Fe4S] cofactor is to ensure the delivery of packages of two electrons to the reactant.

Worse histopathology and prognosis in women with breast cancer diagnosed during the second trimester of pregnancy.

BACKGROUND: Evidence suggests that women with breast cancer diagnosed during pregnancy (PrBC) and within 2 years of delivery (PPBC) have similar survival compared to women diagnosed not near pregnancy if adjusted for stage and subtype. To investigate whether this is true for all subtypes and for both pregnancy and post-delivery periods, we examined clinicopathologic features and survival in women with breast cancer by trimesters and 6-month post-delivery intervals. MATERIALS AND METHODS: Women diagnosed with invasive breast cancer during 1992-2018 at ages 18-44 years were identified in the Swedish Cancer Register, with information on childbirths from the Swedish Multi-Generation Register and clinical data from Breast Cancer Quality Registers. Each woman with PrBC or PPBC was matched 1 : 2 by age and year to comparators diagnosed with breast cancer not near pregnancy. Distributions of stage, grade, and surrogate subtypes were compared. Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for breast cancer mortality were estimated using Cox regression. RESULTS: We identified 1430 women with PrBC and PPBC (181 during pregnancy, 499 during the first and 750 during the second year after delivery). Compared to 2860 comparators, women with PrBC and PPBC in the first year after delivery had a significantly higher proportion of luminal human epidermal growth factor receptor 2 (HER2)-positive, HER2-positive and triple-negative tumours, and more advanced stage at diagnosis. After adjustment for age, year, parity, country of birth, hospital region, subtype, and stage, women diagnosed during the second trimester had a worse prognosis than matched comparators (HR 1.8, 95% CI: 1.0-3.2). CONCLUSIONS: Women diagnosed during pregnancy or within the first year after delivery have a worse prognosis than women diagnosed not near pregnancy due to adverse tumour biology and advanced stage at diagnosis. A worse prognosis for women diagnosed during the second trimester remained after multivariable adjustment, possibly reflecting difficulties to provide optimal treatment during ongoing pregnancy.

ESMO Expert Consensus Statements on the management of breast cancer during pregnancy (PrBC).

The management of breast cancer during pregnancy (PrBC) is a relatively rare indication and an area where no or little evidence is available since randomized controlled trials cannot be conducted. In general, advances related to breast cancer (BC) treatment outside pregnancy cannot always be translated to PrBC, because both the interests of the mother and of the unborn should be considered. Evidence remains limited and/or conflicting in some specific areas where the optimal approach remains controversial. In 2022, the European Society for Medical Oncology (ESMO) held a virtual consensus-building process on this topic to gain insights from a multidisciplinary group of experts and develop statements on controversial topics that cannot be adequately addressed in the current evidence-based ESMO Clinical Practice Guideline. The aim of this consensus-building process was to discuss controversial issues relating to the management of patients with PrBC. The virtual meeting included a multidisciplinary panel of 24 leading experts from 13 countries and was chaired by S. Loibl and F. Amant. All experts were allocated to one of four different working groups. Each working group covered a specific subject area with two chairs appointed: Planning, preparation and execution of the consensus process was conducted according to the ESMO standard operating procedures.

Population-based cohort study of oral contraceptive use and risk of depression.

AIM: Research on the effect of oral contraceptive (OC) use on the risk of depression shows inconsistent findings, especially in adult OC users. One possible reason for this inconsistency is the omission of women who discontinue OCs due to adverse mood effects, leading to healthy user bias. To address this issue, we aim to estimate the risk of depression that is associated with the initiation of OCs as well as the effect of OC use on lifetime risk of depression. METHODS: This is a population-based cohort study based on data from 264,557 women from the UK Biobank. Incidence of depression was addressed via interviews, inpatient hospital or primary care data. The hazard ratio (HR) between OC use and incident depression was estimated by multivariable Cox regression with OC use as a time-varying exposure. To validate causality, we examined familial confounding in 7,354 sibling pairs. RESULTS: We observed that the first 2 years of OC use were associated with a higher rate of depression compared to never users (HR = 1.71, 95% confidence interval [CI]: 1.55-1.88). Although the risk was not as pronounced beyond the first 2 years, ever OC use was still associated with an increased lifetime risk of depression (HR = 1.05, 95% CI: 1.01-1.09). Previous OC use were associated with a higher rate of depression compared to never users, with adolescent OC users driving the increased hazard (HR = 1.18, 95% CI: 1.12-1.25). No significant association were observed among adult OC users who had previously used OCs (HR = 1.00, 95% CI: 0.95-1.04). Notably, the sibling analysis provided further evidence for a causal effect of OC use on the risk of depression. CONCLUSIONS: Our findings suggest that the use of OCs, particularly during the first 2 years, increases the risk of depression. Additionally, OC use during adolescence might increase the risk of depression later in life. Our results are consistent with a causal relationship between OC use and depression, as supported by the sibling analysis. This study highlights the importance of considering the healthy user bias as well as family-level confounding in studies of OC use and mental health outcomes. Physicians and patients should be aware of this potential risk when considering OCs, and individualized risk-benefit assessments should be conducted.

Automated surveillance systems for healthcare-associated infections: results from a European survey and experiences from real-life utilization.

BACKGROUND: As most automated surveillance (AS) methods to detect healthcare-associated infections (HAIs) have been developed and implemented in research settings, information about the feasibility of large-scale implementation is scarce. AIM: To describe key aspects of the design of AS systems and implementation in European institutions and hospitals. METHODS: An online survey was distributed via e-mail in February/March 2019 among (i) PRAISE (Providing a Roadmap for Automated Infection Surveillance in Europe) network members; (ii) corresponding authors of peer-reviewed European publications on existing AS systems; and (iii) the mailing list of national infection prevention and control focal points of the European Centre for Disease Prevention and Control. Three AS systems from the survey were selected, based on quintessential features, for in-depth review focusing on implementation in practice. FINDINGS: Through the survey and the review of three selected AS systems, notable differences regarding the methods, algorithms, data sources, and targeted HAIs were identified. The majority of AS systems used a classification algorithm for semi-automated surveillance and targeted HAIs were mostly surgical site infections, urinary tract infections, sepsis, or other bloodstream infections. AS systems yielded a reduction of workload for hospital staff. Principal barriers of implementation were strict data security regulations as well as creating and maintaining an information technology infrastructure. CONCLUSION: AS in Europe is characterized by heterogeneity in methods and surveillance targets. To allow for comparisons and encourage homogenization, future publications on AS systems should provide detailed information on source data, methods, and the state of implementation.

Technological readiness and implementation of genomic-driven precision medicine for complex diseases.

The fields of human genetics and genomics have generated considerable knowledge about the mechanistic basis of many diseases. Genomic approaches to diagnosis, prognostication, prevention and treatment - genomic-driven precision medicine (GDPM) - may help optimize medical practice. Here, we provide a comprehensive review of GDPM of complex diseases across major medical specialties. We focus on technological readiness: how rapidly a test can be implemented into health care. Although these areas of medicine are diverse, key similarities exist across almost all areas. Many medical areas have, within their standards of care, at least one GDPM test for a genetic variant of strong effect that aids the identification/diagnosis of a more homogeneous subset within a larger disease group or identifies a subset with different therapeutic requirements. However, for almost all complex diseases, the majority of patients do not carry established single-gene mutations with large effects. Thus, research is underway that seeks to determine the polygenic basis of many complex diseases. Nevertheless, most complex diseases are caused by the interplay of genetic, behavioural and environmental risk factors, which will likely necessitate models for prediction and diagnosis that incorporate genetic and non-genetic data.

Recurrence and survival after standard versus oncoplastic breast-conserving surgery for breast cancer.

BACKGROUND: Oncoplastic techniques in breast-conserving surgery (BCS) are used increasingly for larger tumours. This large cohort study aimed to assess oncological outcomes after oncoplastic BCS (OPS) versus standard BCS. METHODS: Data for all women who had BCS in three centres in Stockholm during 2010-2016 were extracted from the Swedish National Breast Cancer Register. All patients with T2-3 tumours, all those receiving neoadjuvant treatment, and an additional random sample of women with T1 tumours were selected. Medical charts were reviewed for local recurrences and surgical technique according to the Hoffman-Wallwiener classification. Date and cause of death were retrieved from the Swedish Cause of Death Register. RESULTS: The final cohort of 4178 breast cancers in 4135 patients was categorized into three groups according to surgical technique: 3720 for standard BCS, 243 simple OPS, and 215 complex OPS. Median duration of follow up was 64 (range 24-110) months. Node-positive and large tumours were more common in OPS than in standard BCS (P < 0.001). There were 61 local recurrences: 57 (1.5 per cent), 1 (0.4 per cent) and 3 (1.4 per cent) in the standard BCS, simple OPS and complex OPS groups respectively (P = 0.368). Overall, 297 patients died, with an unadjusted 5-year overall survival rate of 94.7, 93.1 and 92.6 per cent respectively (P = 0.350). Some 102 deaths were from breast cancer, with unadjusted 5-year cancer-specific survival rates of 97.9, 98.3 and 95.0 per cent respectively (P = 0.056). DISCUSSION: Oncoplastic BCS is a safe surgical option, even for larger node-positive tumours, with low recurrence and excellent survival rates.

Reaction mechanism catalyzed by the dissimilatory adenosine 5'-phosphosulfate reductase. Adenosine 5'-monophosphate inhibitor and key role of arginine 317 in switching the course of catalysis.

The present research is a continuation of our work on dissimilatory reduction pathway of sulfate - involved in biogeochemical sulfur turnover. Adenosine 5'-phosphosulfate reductase (APSR) is the second enzyme in the dissimilatory pathway of the sulfate to sulfide reduction. It reversibly catalyzes formation of the sulfite anion (HSO3-) from adenosine 5'-phosphosulfate (APS) - the activated form of sulfate provided by ATP sulfurylase (ATPS). Two electrons required for this redox reaction derive from reduced FAD cofactor, which is suggested to be involved directly in the catalysis by formation of FADH-SO3- intermediate. The present work covers quantum-mechanical (QM) studies on APSR reaction performed for eight models of APSR active site. The cluster models were constructed based on two crystal structures (PDB codes: 2FJA and 2FJB), differing in conformation of Arg317 active site residue. The described results indicated the most feasible mechanism of APSR forward reaction, including formation of FADHN-SO3- adduct (with proton on N5 atom of isoalloxazine), tautomerization of FADHN-SO3- to FADHO-SO3- (with proton on CO moiety of isoalloxazine), and its reductive cleavage to oxidized FAD and sulfite anion. The reverse reaction proceeds in the backward direction. It is suggested that it requires two AMP molecules, one acting as a substrate and another as an inhibitor of forward reaction, which forces change of Arg317 conformation from "arginine in" (2FJA) to "arginine out" (2FJB). Important role of Arg317 in switching the course of the APSR catalytic reaction is revealed by changing the direction of thermodynamic driving force. The presented research also shows the importance of the protonation pattern of the reduced FAD cofactor and protein residues within the active site.

Immunoglobulins as Biomarkers for Gastrointestinal Nematodes Resistance in Small Ruminants: A systematic review.

The rise of anthelmintic resistance worldwide has led to the development of alternative control strategies for gastrointestinal nematodes (GIN) infections, which are one of the main constraints on the health of grazing small ruminants. Presently, breeding schemes rely mainly on fecal egg count (FEC) measurements on infected animals which are time-consuming and requires expertise in parasitology. Identifying and understanding the role of immunoglobulins in the mechanisms of resistance could provide a more efficient and sustainable method of identifying nematode-resistant animals for selection. In this study we review the findings on immunoglobulin response to GIN in the literature published to date (june 2019) and discuss the potential to use immunoglobulins as biomarkers. The literature review revealed 41 studies which measured at least one immunoglobulin: 35 focused on lamb immune response (18 used non-naïve lambs) and 7 on yearlings. In this review we propose a conceptual model summarizing the role of immunoglobulins in resistance to GIN. We highlight the need for more carefully designed and documented studies to allow comparisons across different populations on the immunoglobulin response to GIN infection.

The importance of sample size with regard to the robustness of postmortem reference values.

Evaluating postmortem toxicological results is a challenging task due to multiple factors affecting blood concentrations after death. In order to improve the diagnostic accuracy in cases of suspected fatal intoxication different compilations of postmortem reference drug concentrations are often used. However, it is not clear what constitutes a reliable postmortem reference value. The current study presents reference concentrations for 13 substances from seven substance groups according to a standardized protocol. The reference concentrations were gathered from 3767 autopsy cases and subdivided into intoxications by one substance only (Group A, n=611), multi-substance intoxications (Group B, n=1355) and postmortem controls, in which incapacitation by drugs were excluded (Group C, n=1801). In particular, this study presents statistical information about the precision and conformity change with various sample sizes. Based on the present data >10 detections are usually needed, for the substances examined, to differentiate between intoxication cases and controls. Repeated samplings show that the median of small samples (N=≤5) has a high variation (normalized interquartile range 138-75%) and that a high number of detections (N=>20) in each group are needed to reduce the variation.

Mutations in ASIP and MC1R: dominant black and recessive black alleles segregate in native Swedish sheep populations.

By studying genes associated with coat colour, we can understand the role of these genes in pigmentation but also gain insight into selection history. North European short-tailed sheep, including Swedish breeds, have variation in their coat colour, making them good models to expand current knowledge of mutations associated with coat colour in sheep. We studied ASIP and MC1R, two genes with known roles in pigmentation, and their association with black coat colour. We did this by sequencing the coding regions of ASIP in 149 animals and MC1R in 129 animals from seven native Swedish sheep breeds in individuals with black, white or grey fleece. Previously known mutations in ASIP [recessive black allele: g.100_105del (D5 ) and/or g.5172T>A] were associated with black coat colour in Klövsjö and Roslag sheep breeds and mutations in both ASIP and MC1R (dominant black allele: c.218T>A and/or c.361G>A) were associated with black coat colour in Swedish Finewool. In Gotland, Gute, Värmland and Helsinge sheep breeds, coat colour inheritance was more complex: only 11 of 16 individuals with black fleece had genotypes that could explain their black colour. These breeds have grey individuals in their populations, and grey is believed to be a result of mutations and allelic copy number variation within the ASIP duplication, which could be a possible explanation for the lack of a clear inheritance pattern in these breeds. Finally, we found a novel missense mutation in MC1R (c.452G>A) in Gotland, Gute and Värmland sheep and evidence of a duplication of MC1R in Gotland sheep.

Gynecologic cancers in pregnancy: guidelines based on a third international consensus meeting.

We aimed to provide comprehensive protocols and promote effective management of pregnant women with gynecological cancers. New insights and more experience have been gained since the previous guidelines were published in 2014. Members of the International Network on Cancer, Infertility and Pregnancy (INCIP), in collaboration with other international experts, reviewed existing literature on their respective areas of expertise. Summaries were subsequently merged into a manuscript that served as a basis for discussion during the consensus meeting. Treatment of gynecological cancers during pregnancy is attainable if management is achieved by collaboration of a multidisciplinary team of health care providers. This allows further optimization of maternal treatment, while considering fetal development and providing psychological support and long-term follow-up of the infants. Nonionizing imaging procedures are preferred diagnostic procedures, but limited ionizing imaging methods can be allowed if indispensable for treatment plans. In contrast to other cancers, standard surgery for gynecological cancers often needs to be adapted according to cancer type and gestational age. Most standard regimens of chemotherapy can be administered after 14 weeks gestational age but are not recommended beyond 35 weeks. C-section is recommended for most cervical and vulvar cancers, whereas vaginal delivery is allowed in most ovarian cancers. Breast-feeding should be avoided with ongoing chemotherapeutic, endocrine or targeted treatment. More studies that focus on the long-term toxic effects of gynecologic cancer treatments are needed to provide a full understanding of their fetal impact. In particular, data on targeted therapies that are becoming standard of care in certain gynecological malignancies is still limited. Furthermore, more studies aimed at the definition of the exact prognosis of patients after antenatal cancer treatment are warranted. Participation in existing registries (www.cancerinpregnancy.org) and the creation of national tumor boards with multidisciplinary teams of care providers (supplementary Box S1, available at Annals of Oncology online) is encouraged.

Mechanism of Sulfate Activation Catalyzed by ATP Sulfurylase - Magnesium Inhibits the Activity.

ATPS Sulfurylase (ATPS) is the first of three enzymes in the sulfate reduction pathway - one of the oldest metabolic pathways on Earth, utilized by Sulfate Reducing Bacteria (SRB). Due to the low redox potential of the sulfate ion, its reduction requires activation via formation of adenosine 5'-phosphosulfate (APS), which is catalyzed by ATPS. Dispersion-corrected hybrid density functional theory (DFT/B3LYP-D3) was used to test three reaction mechanisms proposed for conversion of ATP to APS: two-step SN-1 reaction running through AMP anhydride intermediate, two-step reaction involving cyclic AMP intermediate and direct SN-2 conversion of ATP to APS molecule. The study employed five different cluster models of the ATPS active site: one containing magnesium cation and four without it, constructed based on the crystal structure (PDB code: 1G8H) solved for ATPS from Saccharomyces cerevisiae in complex with APS and pyrophosphate (PPi), where Mg2+ was not detected. The model with magnesium ion was constructed based on the representative structure obtained from trajectory analysis of the molecular dynamics simulations (MD) performed for the hexameric ATPS-APS-Mg2+-PPi complex. The results obtained for all considered models suggest that ATPS-AMP anhydride intermediate is a highly energetic and unstable complex, while formation of cyclic AMP molecule requires formation of unfavorable hypervalent geometry at the transition state. Among all tested mechanism, the energetically most feasible mechanism of the ATPS reaction is SN-2 one-step conversion of ATP to APS occurring via a pentavalent transition state. Interestingly, such a reaction is inhibited by the presence of Mg2+ in the ATPS active site. Magnesium cation forces unfavorable geometry of reactants for SN-2 mechanism and formation of pentavalent transition state. Such a reaction requires rearrangement of Mg2+ ligands, which raises the barrier from 11-14 kcal/mol for the models without Mg2+ to 48 kcal/mol for model with magnesium ion included.

Winter storms accelerate the demise of sea ice in the Atlantic sector of the Arctic Ocean.

A large retreat of sea-ice in the 'stormy' Atlantic Sector of the Arctic Ocean has become evident through a series of record minima for the winter maximum sea-ice extent since 2015. Results from the Norwegian young sea ICE (N-ICE2015) expedition, a five-month-long (Jan-Jun) drifting ice station in first and second year pack-ice north of Svalbard, showcase how sea-ice in this region is frequently affected by passing winter storms. Here we synthesise the interdisciplinary N-ICE2015 dataset, including independent observations of the atmosphere, snow, sea-ice, ocean, and ecosystem. We build upon recent results and illustrate the different mechanisms through which winter storms impact the coupled Arctic sea-ice system. These short-lived and episodic synoptic-scale events transport pulses of heat and moisture into the Arctic, which temporarily reduce radiative cooling and henceforth ice growth. Cumulative snowfall from each sequential storm deepens the snow pack and insulates the sea-ice, further inhibiting ice growth throughout the remaining winter season. Strong winds fracture the ice cover, enhance ocean-ice-atmosphere heat fluxes, and make the ice more susceptible to lateral melt. In conclusion, the legacy of Arctic winter storms for sea-ice and the ice-associated ecosystem in the Atlantic Sector lasts far beyond their short lifespan.

Range of motion in the talo-navicular and the calcaneo-cuboid joints evaluated by ultrasound during clubfoot treatment with normal references up to the age of four years.

PURPOSE: Previous ultrasound studies of clubfeet have mainly focused on the first year of life. The purpose of this study was to improve the evaluation of the talo-navicular and calcaneo-cuboid joints by adding new variables, evaluating the repeatability of ultrasound measurements for normal feet and clubfeet and establishing values for normal feet up to four years of age. METHODS: A control group of 105 children divided into ten age groups, and 71 clubfeet in 46 children were examined. Four new variables were introduced: medial malleolus-Talar head-Navicular distance, medial tangent of the talus to the medial border of the navicular distance, the angle between the longitudinal axis of the talus and a line from the centre of the talar head to the medial corner of the navicular, the angle between the lateral borders of the calcaneus and the cuboid. The mobility in the talo-navicular and the calcaneo-cuboid joints was assessed by comparing measurements with the foot in adduction and abduction. RESULTS: The variables could be assessed with fair to very good intra- and inter-observer repeatability (intraclass correlation coefficient > 0.8 and ≥ 0.6, respectively), with a few exceptions. There was less movement in talo-navicular and calcaneo-cuboid joints in clubfeet than in controls. CONCLUSION: Morphology of normal feet and clubfeet, as well as mobility in the talo-navicular and calcaneo-cuboid joints, can be assessed by ultrasound with a fair to very good reliability from birth to the age of four years. LEVEL OF EVIDENCE: III.

Coinfections identified from metagenomic analysis of cervical lymph nodes from tularemia patients.

BACKGROUND: Underlying coinfections may complicate infectious disease states but commonly go unnoticed because an a priori clinical suspicion is usually required so they can be detected via targeted diagnostic tools. Shotgun metagenomics is a broad diagnostic tool that can be useful for identifying multiple microbes simultaneously especially if coupled with lymph node aspirates, a clinical matrix known to house disparate pathogens. The objective of this study was to analyze the utility of this unconventional diagnostic approach (shotgun metagenomics) using clinical samples from human tularemia cases as a test model. Tularemia, caused by the bacterium Francisella tularensis, is an emerging infectious disease in Turkey. This disease commonly manifests as swelling of the lymph nodes nearest to the entry of infection. Because swollen cervical nodes are observed from many different types of human infections we used these clinical sample types to analyze the utility of shotgun metagenomics. METHODS: We conducted an unbiased molecular survey using shotgun metagenomics sequencing of DNA extracts from fine-needle aspirates of neck lymph nodes from eight tularemia patients who displayed protracted symptoms. The resulting metagenomics data were searched for microbial sequences (bacterial and viral). RESULTS: F. tularensis sequences were detected in all samples. In addition, we detected DNA of other known pathogens in three patients. Both Hepatitis B virus (HBV) and Human Parvovirus B-19 were detected in one individual and Human Parvovirus B-19 alone was detected in two other individuals. Subsequent PCR coupled with Sanger sequencing verified the metagenomics results. The HBV status was independently confirmed via serological diagnostics, despite evading notice during the initial assessment. CONCLUSION: Our data highlight that shotgun metagenomics of fine-needle lymph node aspirates is a promising clinical diagnostic strategy to identify coinfections. Given the feasibility of the diagnostic approach demonstrated here, further steps to promote integration of this type of diagnostic capability into mainstream clinical practice are warranted.

Assessment of the ankle joint in clubfeet and normal feet to the age of four years by ultrasonography.

PURPOSE: To establish reproducible posterior ultrasonographic projections for evaluation of the movement in the talocrural joint in clubfeet and normal feet from the perinatal period up to the age of four years. METHODS: The feet in 105 healthy children and 46 patients (71 clubfeet and 21 normal feet) were examined. In all, 14 feet in seven patients were examined twice by two examiners independently to evaluate the repeatability of the ultrasonography scans. A posterior sagittal projection was used. The distance from the posterior aspect of the tibial physis to the posterior border of the talocalcaneal joint (Tib. phys - TCJ) was measured with the foot in neutral position and dorsiflexion. In plantar flexion the shortest distance between the tibial physis and the calcaneus was measured. The distance from the skin to the tibial epiphyses and the talus was measured in neutral position. The intraclass correlation coefficient (ICC) was calculated to evaluate the repeatability of the measurements. RESULTS: The interexaminer reliability was 0.71 to 0.89 ICC. The intra- and interobserver reliability measured as ICC was 0.68 to 0.99 for all measurements. The correlation between Tib. phys. - TCJ and clinical dorsiflexion varied much between the age groups. CONCLUSION: Ultrasonography of the posterior aspect of the ankle joint can be done with high interexaminer reliability. The repeatability of image evaluation was high. Correlation to clinical measurements varied, therefore dynamic ultrasound in real time is clinically more useful than single measurements on frozen ultrasound images.

The Parkinson's Disease Composite Scale: results of the first validation study.

BACKGROUND AND PURPOSE: The aim was to validate the Parkinson's Disease Composite Scale (PDCS). METHODS: The study included 194 Parkinson's disease (PD) patients in five countries. Investigators completed the following scales: PDCS, the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), Parkinson's Disease Sleep Scale Version 2, Montreal Cognitive Assessment, the Scale for Evaluation of Neuropsychiatric Disorders in Parkinson's Disease and the Clinical Impression of Severity Index for PD (CISI-PD). For test-retest analysis, a second administration of the PDCS was carried out in 61 stable patients (as per the CISI-PD) in 7-14 days after the first evaluation. The PDCS is a novel scale for PD with a total of 17 items divided into four domains: motor, non-motor, treatment complications and disability. RESULTS: Parkinson's Disease Composite Scale mean and median values were close. Skewness values were into the criterion limits (-1 to +1). The complete range of scores was covered for 14 of the 17 items (83.4%). A floor effect of 25.26% and 28.25% was observed in the complications and disability level dimensions due to the proportion of patients free of these difficulties. No relevant floor or ceiling effect was observed for the PDCS total score (1.03% and 0.52%, respectively). The stability of the scale appeared excellent with most items meeting weighted kappa and intraclass correlation coefficient values >0.80. The convergent validity of the PDCS with corresponding scores of the MDS-UPDRS showed high correlation values (rS  ≥ 0.60). The internal validity was into acceptable limits, with the majority of values higher than the minimal 0.30 threshold. The standard error of measurement suggested a satisfactory precision (SEM 3.81, <30% of the PDCS total score standard deviation). CONCLUSION: The PDCS appears to be a feasible, acceptable, reproducible and valid scale.