GPs' interest in integrated care for frail older adults and corresponding consulting and prescribing data: qualitative and quantitative analyses of the PAERPA integrated care project.

BACKGROUND: Integrated care pathways can help to avoid unnecessary admissions to hospital and improve the overall quality of care for frail older patients. Although these integrated care pathways should be coordinated by GPs their level of commitment may vary. AIM: To profile GPs who had participated or had declined to participate in the Personnes Agées En Risque de Perte d'Autonomie (PAERPA) integrated care project (ICP) in the Valenciennois-Quercitain area of France between 2014 and 2019. DESIGN AND SETTING: A combined qualitative and quantitative analysis of GPs who were participating in or had declined to participate in the PAERPA ICP. METHOD: Both GPs participating in the ICP and GPs who chose not to participate in the ICP were interviewed, and then consultation and prescription profiles for these two groups were compared. RESULTS: Some GPs were interested in the PAERPA ICP, whereas others were opposed. The 48 qualitative interviews revealed four issues that influenced participation in the PAERPA ICP: 1) awareness of issues in care of older adults and the value of collaborative work; 2) time saving; 3) task delegation; and 4) advantages of coordination. The level of interest in the ICP for frail older adults was indirectly reflected by the data on consulting and prescribing. In GPs who participated in the PAERPA ICP there was a greater proportion of older (aged ≥70 years) patients (P<0.05), a larger number of consultations per year (P<0.05), and a larger number of home visits (P<0.01), relative to GPs who declined to participate. CONCLUSION: The level of interest in the PAERPA ICP for frail older adults varied widely among GPs. These findings suggest that commitment to an integrated care pathway could be increased by customising the recruitment strategy as a function of the GP's profile.

Acoustic Change Over Time in Spastic and/or Flaccid Dysarthria in Motor Neuron Diseases.

PURPOSE: This study aims to investigate acoustic change over time as biomarkers to differentiate among spastic-flaccid dysarthria associated with amyotrophic lateral sclerosis (ALS), spastic dysarthria associated with primary lateral sclerosis (PLS), flaccid dysarthria associated with spinal and bulbar muscular atrophy (SBMA), and to explore how these acoustic parameters are affected by dysarthria severity. METHOD: Thirty-three ALS patients with mixed flaccid-spastic dysarthria, 17 PLS patients with pure spastic dysarthria, 18 SBMA patients with pure flaccid dysarthria, and 70 controls, all French speakers, were included in the study. Speakers produced vowel-glide sequences targeting different vocal tract shape changes. The mean and coefficient of variation of the total squared change of mel frequency cepstral coefficients were used to capture the degree and variability of acoustic changes linked to vocal tract modifications over time. Differences in duration of acoustic events were also measured. RESULTS: All pathological groups showed significantly less acoustic change compared to controls, reflecting less acoustic contrast in sequences. Spastic and mixed spastic-flaccid dysarthric speakers showed smaller acoustic changes and slower sequence production compared to flaccid dysarthria. For dysarthria subtypes associated with a spastic component, reduced degree of acoustic change was also associated with dysarthria severity. CONCLUSIONS: The acoustic parameters partially differentiated among the dysarthria subtypes in relation to motor neuron diseases. While similar acoustic patterns were found in spastic-flaccid and spastic dysarthria, crucial differences were found between these two subtypes relating to variability. The acoustic patterns were much more variable in ALS. This method forms a promising clinical tool as a diagnostic marker of articulatory impairment, even at mild stage of dysarthria progression in all subtypes.

Barriers and Facilitators in the Uptake of Integrated Care Pathways for Older Patients by Healthcare Professionals: A Qualitative Analysis of the French National "Health Pathway of Seniors for Preserved Autonomy" Pilot Program: Barriers and Facilitators for Adhesion of Healthcare Professionals in Integrated Care for Older Patients: A Qualitative Assessment Based on the French National Experiment: 'Health Pathway of Seniors for Preserved Autonomy' (PAERPA).

INTRODUCTION: Integrated care is a particularly promising approach in geriatrics - a field in which the medical, psychological and social issues are often complex. The uptake of integrated care by healthcare professionals (HCPs) is essential but varies markedly. The objective of the present study of healthcare professionals was to identify barriers to and facilitators of commitment to integrated care for seniors. METHODS: We performed a two-step, qualitative study, comprising (i) six qualitative, semi-directive series of interviews with HCPs (hospital practitioners, family physicians, nurses and pharmacists) who agreed or disagreed to take part in the French national "Health Pathway of Seniors for Preserved Autonomy" (PAERPA) pilot program; and (ii) an analysis of the pooled results, in order to identify common concerns among the healthcare professionals. RESULTS: We identified four key "barrier" and "facilitator" topics shared by HCPs who had committed to the pilot program and those who had not: (i) awareness of and/or interest in geriatric medicine and team working, (ii) the presence of a care coordinator; (iii) the provision of information about the program and about the patient, and communication between HCPs, and (iv) personal benefits for the HCPs and the patients. KEY CONCLUSIONS: The four key topics identified in this large qualitative study of several healthcare professions should be considered during the design and dissemination of integrated care pathways for older patients.

Sensitivity and specificity of an acoustic- and perceptual-based tool for assessing motor speech disorders in French: the MonPaGe-screening protocol.

To respond to the need of objective screening tools for motor speech disorders (MSD), we present the screening version of a speech assessment protocol (MonPaGe-2.0.s), which is based on semi-automated acoustic and perceptual measures on several speech dimensions in French. We validate the screening tool by testing its sensitivity and specificity and comparing its outcome with external standard assessment tools. The data from 80 patients diagnosed with different types of mild to moderate MSD and 62 healthy test controls were assessed against the normative data obtained on 404 neurotypical speakers, with Deviance Scores computed on seven speech dimensions (voice, speech rate, articulation, prosody, pneumophonatory control, diadochokinetic rate, intelligibility) based on acoustic and perceptual measures. A cut-off of the MonPaGe total deviance score (TotDevS) >2 allowed MSD to be diagnosed with specificity of 95% and an overall sensitivity of 83.8% on all patients pulled, reaching 91% when very mildly impaired patients were excluded. A strong correlation was found between the MonPaGe TotDevS and an external composite perceptual score of MSD provided by six experts. The MonPaGe screening protocol has proven its sensitivity and specificity for diagnosing presence and severity of MSD. Further implementations are needed to complement the characterization of impaired dimensions in order to distinguish subtypes of MSD.

Simultaneous determination of all forms of biopterin and neopterin in cerebrospinal fluid.

In humans, genetic defects of the synthesis or regeneration of tetrahydrobiopterin (BH4), an essential cofactor in hydroxylation reactions, are associated with severe neurological disorders. The diagnosis of these conditions relies on the determination of BH4, dihydrobiopterin (BH2), and dihydroneopterin (NH2) in cerebrospinal fluid (CSF). As MS/MS is less sensitive than fluorescence detection (FD) for this purpose, the most widely used method since 1980 involves two HPLC runs including two differential off-line chemical oxidation procedures aiming to transform the reduced pterins into their fully oxidized fluorescent counterparts, biopterin (B) and neopterin (N). However, this tedious and time-consuming two-step indirect method underestimates BH4, BH2, and NH2 concentrations. Direct quantification of BH4 is essential for studying its metabolism and for monitoring the efficacy of BH4 supplementation in patients with genetic defects. Here we describe a single step method to simultaneously measure BH4, BH2, B, NH2, and N in CSF by HPLC coupled to FD after postcolumn coulometric oxidation. All target pterins were quantified in CSF with a small volume (100 µL), and a single filtration step for sample preparation and analysis. As compared to the most widely used method in more than 100 CSF samples, this new assay is the easiest route for accurately determining in a single run BH4, BH2, and NH2 in CSF in deficit situations as well as for monitoring the efficacy of the treatment.

An electrospray ionisation-mass spectrometry screening of triacylglycerols in developing cultivated and wild peanut kernels (Arachis hypogaea L.).

The accumulation of triacylglycerols during the development of three varieties of peanuts was monitored in two Tunisian cultivated peanut (Trabelsia (AraT) and Chounfakhi (AraC)) and one wild Tunisian peanut (Arbi (AraA)). The presence of TAGs composed of rare fatty acid residues such as hexacosanoic acid (C(23:0)) and heneicosanoic acid (C(21:0)) among the triacylglycerols C(23:0) LL, C(23:0) OO and C(21:0) LL was noted. The major molecular species of triacylglycerol detected in the three peanut varieties were dioleoyl linoleoyl (OOL), 1,2,3-trioleyl (OOO), 1,2-dioleyl-3-palmitoyl (POO), 1,2-dilinoleoyl-3-oleyl (OLL) and 1-oleoyl-2-linoleoyl-3-linolenoyl (OLLn). The TAG composition and content were significantly different among the three peanut varieties. The three major TAGs were OOL (20.6%), OOO (15.6%) and OLLn (13.2%) in AraA; OOL (21.4%), OOO (20.1%) and POO (17.5%) in AraC and finally OLL (20.7%), OOO (19.8%) and OLL (17.7%) in AraT.

Validation of robust tools to measure sialorrhea in amyotrophic lateral sclerosis: a study in a large French cohort.

There is an unmet need for validated tools to measure sialorrhea in amyotrophic lateral sclerosis, especially to evaluate treatments. We assessed the inter-/intra-rate reviewer reliability of two scales: the Oral Secretion Scale (OSS), specifically developed for ALS patients, and the Sialorrhea Scoring Scale (SSS), initially developed for Parkinson's disease patients. Sialorrhea was rated in 69 ALS consecutive patients by four evaluators: two neurologists, one nurse and one speech therapist. Inter-rater reliability was evaluated by the light kappa coefficient and intra-rater reliability by the weighted kappa coefficient. We also compared patients' and caregivers' answers. Results demonstrated that the two scales present a high inter-/intra-rater reliability: weighted kappas were 0.85 for both scales and light kappas 0.89 for the OSS and 0.88 for the SSS. Both scales also showed a good intra-profession reliability (OSS kappa = 0.84; SSS kappa = 0.79) and agreement between patients' and caregivers' answers. The SSS showed a higher responsiveness compared to OSS. In conclusion, both Oral Secretion Scale and Sialorrhea Scoring Scale are reliable tools to measure sialorrhea in ALS patients. Because of the wide range of salivation degrees, SSS may be more sensitive as a tool to evaluate treatments in patients with severe hypersialorrhea.

Determination of triacylglycerol regioisomers using electrospray ionization-quadrupole ion trap mass spectrometry with a kinetic method.

The kinetic method was applied to differentiate and quantify mixtures of regioisomeric triacylglycerols (TAGs) by generating and mass selecting alkali ion bound metal dimeric clusters with a TAG chosen as reference (ref) and examining their competitive dissociations in a quadrupole ion trap mass spectrometer. This methodology readily distinguished pairs of regioisomers (AAB/ABA) such as LLO/LOL, OOP/OPO and SSP/SPS and consequently distinguished sn-1/sn-3, sn-2 substituents on the glycerol backbone. The dimeric complex ions [ref, Li, TAG((AAB and/or ABA))](+) generated by electrospray ionization mass spectrometry were subjected to collision induced dissociation causing competitive loss of either the neutral TAG reference (ref) leading to [Li(AAB and/or ABA)](+) or the neutral TAG molecule (TAG((AAB and/or ABA))) leading to [ref, Li](+). The ratio of the two competitive dissociation rates, defined by the product ion branching ratio (R(iso)), was related via the kinetic method to the regioisomeric composition of the investigated TAG mixture. In this work, a linear correlation was established between composition of the mixture of each TAG regioisomer and the logarithm of the branching ratio for competitive fragmentation. Depending on the availability of at least one TAG regioisomer as standard, the kinetic method and the standard additions method led to the quantitative analysis of natural TAG mixtures.

LC-MS determination of oxidized and reduced glutathione in human dermis: a microdialysis study.

A simple, highly selective, sensitive and reproducible liquid chromatography-electrospray ionization mass spectrometry method has been developed for the direct and simultaneous determination of reduced (GSH) and oxidized (GSSG) glutathione in microdialysis samples from human dermis. Chromatographic separation was carried out on an MODULO CART QS KROMASIL 5C18 (250 mm × 2 mm × 5 µm) analytical column at a flow rate of 0.25 ml/min. An isocratic mode was used and consisted of acidified water and acetonitrile (50/50, v/v). To improve the sensitivity, silver nitrate was added as post-column reagent. A trap mass spectrum was used equipped with an ESI interface. The limits of detection and quantification were respectively 0.12 and 0.4 ng/ml for GSH and 0.2 and 0.5 ng/ml for GSSG. Intra-day and inter-day accuracy and precision were determined and the variability was less than 6.2% (R.S.D.).

Separation and classification of lipids using differential ion mobility spectrometry.

Correlations between the dimensions of a 2-D separation create trend lines that depend on structural or chemical characteristics of the compound class and thus facilitate classification of unknowns. This broadly applies to conventional ion mobility spectrometry (IMS)/mass spectrometry (MS), where the major biomolecular classes (e.g., lipids, peptides, nucleotides) occupy different trend line domains. However, strong correlation between the IMS and MS separations for ions of same charge has impeded finer distinctions. Differential IMS (or FAIMS) is generally less correlated to MS and thus could separate those domains better. We report the first observation of chemical class separation by trend lines using FAIMS, here for lipids. For lipids, FAIMS is indeed more independent of MS than conventional IMS, and subclasses (such as phospho-, glycero-, or sphingolipids) form distinct, often non-overlapping domains. Even finer categories with different functional groups or degrees of unsaturation are often separated. As expected, resolution improves in He-rich gases: at 70% He, glycerolipid isomers with different fatty acid positions can be resolved. These results open the door for application of FAIMS to lipids, particularly in shotgun lipidomics and targeted analyses of bioactive lipids.

Simple complementary liquid chromatography and mass spectrometry approaches for the characterization of triacylglycerols in Pinus koraiensis seed oil.

A new simple strategy to identify triacylglycerols (TAGs) in oils and fats was performed using on line coupling of non aqueous reversed phase chromatography-electrospray ionization-mass spectrometry (NARP-LC-ESI-MS(2)) with silver nitrate (AgNO(3)) as post-column additive, and chromatographic data (partition number information and both the graphs of log k vs. number of double bond (DBN) and carbon number (CN)). NARP liquid chromatography permitted to separate TAGs composed of Δ5 and Δ9 but not from Δ11 double bond location on alkyl chain of fatty acid residues. Silver cationization improved the sensitivity by a factor one hundred. MS(2) information gave unambiguously the nature of three fatty acid residues bonded to glyceryl backbone of TAGs while log k against DBN and CN curves discriminated between the same molecular mass TAG isomers (whose constitutive fatty acid residues are double bond position and configuration isomers). Combination of structural information given by MS with chromatographic retention laws led to the development of a general methodology for determination of the structure of TAGs in lipids. This methodology was applied to Pinus koraiensis seed oil for which some uncommon TAGs are present. It permitted the identification of 58 TAGs in this oil. The experimental proof of 29 uncommon TAGs as component of this oil is demonstrated. Among them 26 were minor constituents.

Regioisomer characterization of triacylglycerols by non-aqueous reversed-phase liquid chromatography/electrospray ionization mass spectrometry using silver nitrate as a postcolumn reagent.

Triacylglycerols (TAGs) provide a challenge for mass spectrometry (MS) analysis because of their complexity. In particular, for dietary, nutritional and metabolic purposes, the positional placement of fatty acids on the glycerol backbone of TAGs is a crucial aspect. To solve this problem, we have investigated the TAGs' fragmentation patterns using an ion trap mass spectrometer. A series of pure regioisomeric pairs of TAGs (POP/PPO, POO/OPO and OSO/SOO) were cationized by Ag(+) after their separation by non-aqueous reversed-phase liquid chromatography (NARP-LC) before MS to improve MS sensitivity. Electrospray ionization-MS (ESI-MS) conditions were optimized in order to produce characteristic [M + Ag + AgNO(3)](+) ions from each TAG, which were then fragmented to produce MS/MS spectra and then fragmented further to produce up to MS(5) spectra. The observation of ions produced by LC-MS(5) of on-line Ag(+)-cationized TAG provided unambiguous information on the fatty acid distribution on the glycerol backbone. These strategies of MS to MS(5) experiments were applied to identify components and to determine the regiospecificity of TAG within a complex mixture of lipids in natural oils.

24 month-treatment with miglustat of three patients with Niemann-Pick disease type C: follow up using brain spectroscopy.

Niemann-Pick C (NPC) is a fatal progressive neurolipidosis. Miglustat, an inhibitor of glycosphingolipid synthesis, has been proposed to treat patients but questions remain regarding its efficacy. A major problem has been the lack of suitable objective efficacy endpoints. Three adults with NPC were treated with miglustat for 24 months. Efficacy of treatment was assessed clinically and using brain magnetic resonance spectroscopy. All patients reported mild clinical improvement or stabilization. Furthermore, a sustained decrease in the choline/creatine ratio was observed in all three patients over time. Although these preliminary results require confirmation on a larger cohort of patients, they suggest that miglustat has some beneficial effect on brain dysfunction in NPC and that MRS could be used routinely as a non invasive surrogate marker of treatment efficacy.

Sensitive method for the quantitative determination of proguanil and its metabolites in rat blood and plasma by liquid chromatography-mass spectrometry.

A sensitive, simple and fast liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method for the determination of proguanil (PG) and its metabolites, cycloguanil (CG) and 1-(4-chlorophenyl)biguanide (4CPB), was developed and validated over a concentration range of 1-2000 ng/mL using only 50 microL of blood or plasma. After a simple solvent precipitation procedure, the supernatant was analysed directly by HPLC-MS/MS. Separation was achieved using an ethyl-linked phenyl reverse phase column with polar endcapping with an acetonitrile-water-formic acid gradient. Mass spectrometry was performed using a triple quadrupole mass spectrometer operating in positive electrospray ionization mode. The elution of PG (254.07-->169.99), CG (252.12-->195.02) and 4CPB (212.06-->153.06) was monitored using selected reaction monitoring. The three compounds and the internal standard (chloroproguanil) were well separated by HPLC and no interfering peaks were detected at the usual concentrations found in blood and plasma. The limit of quantification of PG and CG was 1 ng/mL and 5 ng/mL for 4CPB in rat blood and plasma. The extraction efficiency of PG, CG and 4CPB from rat blood and plasma was higher than 73%. The intra- and inter-assay variability of PG, CG and 4CPB were within 12% and the accuracy within +/-5%. This new assay offers higher sensitivity and a much shorter run time over earlier methods.

Evaluation of a sunscreen photoprotective effect by ascorbic acid assessment in human dermis using microdialysis and gas chromatography mass spectrometry.

Ultraviolet irradiation causes adverse effects like sunburn, photosensitivity reactions or immunologic suppression. The aim of this study was to evaluate the photo-protective outcome of a sunscreen cream (SPF8) by the determination of erythema indexes and the assessment of ascorbic acid and its metabolites in human dermis. These substances were used as markers of oxidative effect. Eight healthy female subjects were enrolled in this study. Two abdominal areas were exposed to solar simulated irradiation with three minimal erythema dose, one with SPF8 application and the other site without SPF8 application. Two other areas were used as control, one without SPF8 application and the other site after SPF8 application. Ascorbic acid and its metabolites (dehydroascorbic acid, threonic acid, oxalic acid and xylose) were collected from human dermis by microdialysis and assessed by gas chromatography mass spectrometry. Irradiated site without sunscreen application had significantly demonstrated lower dermis ascorbic acid concentrations and a higher erythema index than the three other sites (P < 0.05). Threonic acid, oxalic acid and xylose dermis concentrations were significantly higher in site III than in the control site I (P < 0.05). The protected-irradiated site did not show erythema formation and there was stability of ascorbic acid dermis concentrations with non-variation in its metabolites. The assessment of ascorbic acid and its metabolites in human dermis could be an efficient tool to demonstrate the oxidative process and consequently to control the efficiency of sunscreen creams against undesirable UV effects.

In vivo assessment of iron and ascorbic acid in psoriatic dermis.

Reactive oxygen species play an important role in inflammatory skin diseases such as psoriasis. Reactive oxygen species synthesis is catalysed by iron and some species are scavenged by ascorbic acid. The aim of this work was to assess iron and ascorbic acid in uninvolved and involved psoriatic dermis and to compare the corresponding concentrations in the dermis of healthy subjects. Microdialysis associated with atomic absorption spectrometry and gas chromatography-mass spectrometry was used to assess iron and ascorbic acid, respectively. Seven psoriatic patients and five healthy volunteers were studied. Iron concentrations in the involved (57.1 +/- 19.3 microg/l) and uninvolved (49.7 +/- 27.1 microgl/l) psoriatic dermis were higher than the corresponding value determined in the dermis of healthy subjects (21.8 +/- 2.4 microg/l) (p<0.05). Ascorbic acid in involved (47.3 +/- 8.2 microg/ml) and uninvolved (42.0 +/- 14.0 microg/ml) psoriatic dermis was statistically lower than that found in healthy dermis (176.8 +/- 29.0 microg/ml) (p<0.05). These results demonstrate that psoriatic patients exhibit high iron and low ascorbic acid concentrations in the dermis, but there were no significant differences between involved and uninvolved skin.

High iron and low ascorbic acid concentrations in the dermis of atopic dermatitis patients.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease in which reactive oxygen species (ROS) may be involved. Iron catalyses ROS formation and ascorbic acid (AA) scavenges these species. OBJECTIVE: The aim of this work was to determine iron and AA levels in AD patients' dermis and to compare their concentrations with those of healthy volunteers' dermis. METHODS: Five AD patients and 5 healthy subjects (controls) were enrolled in this study. Iron and AA were collected from human dermis by microdialysis and assessed by atomic absorption spectrometry and gas chromatography-mass spectrometry, respectively. RESULTS: The AD dermis demonstrated higher iron concentrations (44.3 +/- 4.6 microg/l) compared to controls (21.8 +/- 1.2 microg/l) as well as a significantly lower concentration of AA (46.7 +/- 0.6 vs. 176.8 +/- 14.5 microg/ml, respectively). CONCLUSION: These results suggest that iron and AA dermis levels could be indicators of inflammatory tissues and might be implicated in dermatological diseases such as AD.

Iron and ascorbic acid concentrations in human dermis with regard to age and body sites.

BACKGROUND: Reactive oxygen species (ROS) contribute to processes relating to cutaneous aging. Iron catalyses ROS formation whereas ascorbic acid (AA) plays a fundamental role in defending the organism against undesirable ROS action. OBJECTIVE: The aim of this work was to determine the ex vivo iron and AA concentrations in human dermis from different age groups to better understand their role. METHODS: Skin fragments were collected from 66 female patients during surgical operations and were grouped according to age: group I (<15 years, before puberty, n = 12), group II (15-50 years, adults, n = 42), and group III (>50 years, advanced age adults, n = 12). Two sites were investigated: the abdomen (unexposed areas) and face (exposed sites). Iron and AA were collected from human dermis by microdialysis and assessed by atomic absorption spectrometry and gas chromatography mass spectrometry, respectively. RESULTS: Iron concentrations in the dermis were significantly higher in group III (27.4 +/- 20.9 microg/l) than in group I (13.8 +/- 3.3 microg/l; p< 0.05 ). An inverse correlation between AA dermis levels and increasing age was detected. For groups III and I, iron and AA concentrations were significantly different in dermis from the face compared to that of the abdomen (p < 0.05). CONCLUSION: This study shows for the first time that there is a direct relationship between iron and AA concentrations in the dermis and aging. Moreover, iron and AA concentrations differed according to body site.

Validation of a microdialysis-gas chromatographic-mass spectrometric method to assess 8-methoxypsoralen in psoriatic patient dermis.

8-Methoxypsoralen (8-MOP) is currently used in PUVA therapy (psoralen+UVA) to treat dermatological diseases such as psoriasis, vitiligo and atopic dermatitis. The aim of this work was to validate a method for collecting 8-MOP from patient dermis by a non invasive technique, microdialysis, and then to assess this molecule by gas chromatography-mass spectrometry (GC-MS). 5-Methoxypsoralen (5-MOP) was used as an internal standard. The calibration curve demonstrated a linear relationship between the peak areas of 8-MOP and 5-MOP over a wide range of 8-MOP concentrations (0.9-100 ng/ml). Within- and between-run precisions were measured, using four different 8-MOP concentrations, which varied from 98.0 to 102.0% and from 98.5 to 101.8%, respectively. The limits of detection and quantification were 0.29 and 0.52 ng/ml, respectively. The method was validated and then applied to determine the pharmacokinetic of 8-MOP in ten psoriatic patient dermis, after oral intake of this drug. The results demonstrated that the association of microdialysis with the GC-MS method was an efficient procedure to collect and assess 8-MOP in human dermis, in vivo.