Meaningful cognitive change for the Minimal Assessment of Cognitive Function in Multiple Sclerosis.

BACKGROUND: There is limited information on interpretation of cognitive changes over time in multiple sclerosis (MS). OBJECTIVE: This study aimed to provide normative data for the assessment of statistically meaningful change in all tests of the Minimal Assessment of Cognitive Function in MS (MACFIMS). METHODS: We applied the reliable change methodology to a healthy Italian cohort, assessed with two alternate versions of the MACFIMS 1 year apart. We calculated confidence intervals of retest score variance using the reliable change index (RCI). Moreover, multivariable linear regression models adjusted for age, sex, education, and baseline score were built to calculate the regression-based change index (RB-CI). RESULTS: Overall, 200 healthy individuals were enrolled. Thresholds for interpreting change in each test were calculated. In the multivariable models, baseline score was associated with retest score in all tests (B from 0.439 to 0.760; p < 0.001). RB-CI can be calculated with data of the multivariable models. CONCLUSION: We provide normative data for reliable cognitive change evaluation for all the tests of the MACFIMS, which includes the Symbol Digit Modalities Test and Brief International Cognitive Assessment in MS, two widely used tools for screening and monitoring cognition in MS. Our findings can significantly improve the interpretation of cognitive changes in MS.

Performance evaluation of the UMIC® Cefiderocol to determine MIC in Gram-negative bacteria.

BACKGROUND: Cefiderocol is a catechol-substituted cephalosporin with potent in vitro activity against carbapenem-resistant (CR) Gram-negative bacteria (GNB). Cefiderocol susceptibility testing is complex because iron concentrations need to be taken into consideration. Here, we assessed the clinical performance of Bruker's UMIC® Cefiderocol and corresponding iron-depleted CAMHB to determine MIC by broth microdilution (BMD) for clinically relevant GNB. METHODS: MICs of cefiderocol for 283 GN clinical isolates were determined by BMD using iron-depleted CAMHB. Frozen panels were used as a reference. The concentration range of cefiderocol was 0.03-32 mg/L. The isolates, with different degrees of susceptibility to cefiderocol, included Enterobacterales (n = 180), Pseudomonas aeruginosa (n = 49), Acinetobacter baumannii (n = 44) and Stenotrophomonas maltophilia (n = 10). RESULTS: The rates of categorical agreement (CA), essential agreement (EA) and bias were calculated to evaluate the performance of the UMIC® Cefiderocol, as compared with the reference method. Overall, the UMIC® Cefiderocol showed 90.8% EA (95% CI: 86.9%-93.7%) with a bias of -14.5% and a CA of 90.1% (95% CI: 86.1%-93.1%). For Enterobacterales, the UMIC® Cefiderocol showed 91.7% EA (95% CI: 86.7%-94.9%) with a bias of -25.0% and a CA of 87.8% (95% CI: 82.2%-91.8%). For non-fermenters, the UMIC® Cefiderocol showed 89.3% EA (95% CI: 81.9%-93.9%) (not significantly different from 90.0%, Student t-test) with a bias of -3.9% and a CA of 94.2% (95% CI: 87.7%-97.3%). CONCLUSIONS: UMIC® Cefiderocol is a valid method for the determination of cefiderocol MICs even if higher than expected discrepancies were observed with NDM-producing Enterobacterales, which presented in most cases MIC values close to the breakpoint.

Effect of BDNF Val66Met polymorphism on hippocampal subfields in multiple sclerosis patients.

Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism was shown to strongly affect BDNF function, but its role in modulating gray matter damage in multiple sclerosis (MS) patients is still not clear. Given BDNF relevance on the hippocampus, we aimed to explore BDNF Val66Met polymorphism effect on hippocampal subfield volumes and its role in cognitive functioning in MS patients. Using a 3T scanner, we obtained dual-echo and 3DT1-weighted sequences from 50 MS patients and 15 healthy controls (HC) consecutively enrolled. MS patients also underwent genotype analysis of BDNF, neurological and neuropsychological evaluation. Hippocampal subfields were segmented by using Freesurfer. The BDNF Val66Met polymorphism was found in 22 MS patients (44%). Compared to HC, MS patients had lower volume in: bilateral hippocampus-amygdala transition area (HATA); cornus ammonis (CA)1, granule cell layer of dentate gyrus (GCL-DG), CA4 and CA3 of the left hippocampal head; molecular layer (ML) of the left hippocampal body; presubiculum of right hippocampal body and right fimbria. Compared to BDNF Val66Val, Val66Met MS patients had higher volume in bilateral hippocampal tail; CA1, ML, CA3, CA4, and GCL-DG of left hippocampal head; CA1, ML, and CA3 of the left hippocampal body; left HATA and presubiculum of the right hippocampal head. In MS patients, higher lesion burden was associated with lower volume of presubiculum of right hippocampal body; lower volume of left hippocampal tail was associated with worse visuospatial memory performance; lower volume of left hippocampal head with worse performance in semantic fluency. Our findings suggest the BNDF Val66Met polymorphism may have a protective role in MS patients against both hippocampal atrophy and cognitive impairment. BDNF genotype might be a potential biomarker for predicting cognitive prognosis, and an interesting target to study for neuroprotective strategies.

Applying multidimensional computerized adaptive testing to the MSQOL-54: a simulation study.

BACKGROUND: The Multiple Sclerosis Quality of Life-54 (MSQOL-54) is one of the most commonly-used MS-specific health-related quality of life (HRQOL) measures. It is a multidimensional, MS-specific HRQOL inventory, which includes the generic SF-36 core items, supplemented with 18 MS-targeted items. Availability of an adaptive short version providing immediate item scoring may improve instrument usability and validity. However, multidimensional computerized adaptive testing (MCAT) has not been previously applied to MSQOL-54 items. We thus aimed to apply MCAT to the MSQOL-54 and assess its performance. METHODS: Responses from a large international sample of 3669 MS patients were assessed. We calibrated 52 (of the 54) items using bifactor graded response model (10 group factors and one general HRQOL factor). Then, eight simulations were run with different termination criteria: standard errors (SE) for the general factor and group factors set to different values, and change in factor estimates from one item to the next set at < 0.01 for both the general and the group factors. Performance of the MCAT was assessed by the number of administered items, root mean square difference (RMSD), and correlation. RESULTS: Eight items were removed due to local dependency. The simulation with SE set to 0.32 (general factor), and no SE thresholds (group factors) provided satisfactory performance: the median number of administered items was 24, RMSD was 0.32, and correlation was 0.94. CONCLUSIONS: Compared to the full-length MSQOL-54, the simulated MCAT required fewer items without losing precision for the general HRQOL factor. Further work is needed to add/integrate/revise MSQOL-54 items in order to make the calibration and MCAT performance efficient also on group factors, so that the MCAT version may be used in clinical practice and research.

Job satisfaction among physicians and nurses involved in the management of multiple sclerosis: the role of happiness and meaning at work.

OBJECTIVE: Health professionals caring for persons with multiple sclerosis (MS) are faced with increasingly complex working conditions that can undermine their job satisfaction and the quality of their healthcare services. The aim of this study was to delve into health professionals' job satisfaction by assessing the predictive role of happiness and meaning at work. Specifically, it was hypothesized that job meaning would moderate the relationship between job happiness and satisfaction. METHODS: The study hypothesis was tested among 108 healthcare professionals (53 physicians and 55 nurses) working in eight MS centers in Italy. Participants were administered the Eudaimonic and Hedonic Happiness Investigation and the Job Satisfaction Questionnaire. Hierarchical regression analysis was performed to test the moderating role of job meaning between job happiness and satisfaction. RESULTS: A significant interaction effect of job happiness and meaning on job satisfaction was identified for both physicians and nurses. When work was attributed low meaning, participants experiencing high job happiness were more satisfied with their work than those reporting low happiness; by contrast, when work was perceived as highly meaningful, participants' levels of job happiness did not significantly contribute to job satisfaction. CONCLUSIONS: Focusing on the interplay between job happiness and meaning, findings bring forward practical suggestions for the preservation and promotion of job satisfaction among health professionals working with MS patients. Particularly, they suggest the need to strengthen those job-related aspects that may enhance job meaning, thus providing health professionals with significant reasons to persevere in their work in the face of daily challenges.

Nosocomial outbreak by NDM-1-producing Klebsiella pneumoniae highly resistant to cefiderocol, Florence, Italy, August 2021 to June 2022.

A nosocomial outbreak by cefiderocol (FDC)-resistant NDM-1-producing Klebsiella pneumoniae (NDM-Kp) occurred in a large tertiary care hospital from August 2021-June 2022 in Florence, Italy, an area where NDM-Kp strains have become endemic. Retrospective analysis of NDM-Kp from cases observed in January 2021-June 2022 revealed that 21/52 were FDC-resistant. The outbreak was mostly sustained by clonal expansion of a mutant with inactivated cirA siderophore receptor gene, which exhibited high-level resistance to FDC (MIC ≥ 32 mg/L) and spread independently of FDC exposure.

Viability of a MSQOL-54 general health-related quality of life score using bifactor model.

BACKGROUND: MSQOL-54 is a multidimensional, widely-used, health-related quality of life (HRQOL) instrument specific for multiple sclerosis (MS). Findings from the validation study suggested that the two MSQOL-54 composite scores are correlated. Given this correlation, it could be assumed that a unique total score of HRQOL may be calculated, with the advantage to provide key stakeholders with a single overall HRQOL score. We aimed to assess how well the bifactor model could account for the MSQOL-54 structure, in order to verify whether a total HRQOL score can be calculated. METHODS: A large international database (3669 MS patients) was used. By means of confirmatory factor analysis, we estimated a bifactor model in which every item loads onto both a general factor and a group factor. Fit of the bifactor model was compared to that of single and two second-order factor models by means of Akaike information and Bayesian information criteria reduction. Reliability of the total and subscale scores was evaluated with Mc Donald's coefficients (omega, and omega hierarchical). RESULTS: The bifactor model outperformed the two second-order factor models in all the statistics. All items loaded satisfactorily (≥ 0.40) on the general HRQOL factor, except the sexual function items. Omega coefficients for total score were very satisfactory (0.98 and 0.87). Omega hierarchical for subscales ranged between 0.22 to 0.57, except for the sexual function (0.70). CONCLUSIONS: The bifactor model is particularly useful when it is intended to acknowledge multidimensionality and at the same time take account of a single general construct, as the HRQOL related to MS. The total raw score can be used as an estimate of the general HRQOL latent score.

The Contribution of Illness Beliefs, Coping Strategies, and Social Support to Perceived Physical Health and Fatigue in Multiple Sclerosis.

This study investigated the relationship of illness beliefs with perceived physical health and fatigue among persons with multiple sclerosis. Besides direct effects between illness beliefs and outcome measures, the mediational role of coping strategies and social support was examined. Six hundred and eighty persons with multiple sclerosis completed the Revised Illness Perception Questionnaire evaluating illness beliefs; the Brief COPE measuring problem-focused, meaning-focused, and avoidant strategies; the Multidimensional Scale of Perceived Social Support assessing social support; MS Quality of Life-54 investigating perceived physical health; and the Fatigue Severity Scale assessing physical fatigue. Mediation analyses were performed controlling for disability level. Direct effects were identified for both perceived physical health and fatigue, whereas indirect effects were observed only for physical health through avoidant strategies and social support. Based on present findings, psychological intervention may primarily target illness beliefs to address fatigue, and beliefs and coping strategies to improve perceived physical health.

Assessing measurement invariance of MSQOL-54 across Italian and English versions.

PURPOSE: The Multiple Sclerosis Quality of Life-54 (MSQOL-54) is a specific multiple sclerosis (MS) health-related quality of life inventory consisting of 52 items organized into 12 subscales plus two single items. No study was found in literature assessing its measurement invariance across language versions. We investigated whether MSQOL-54 items provide unbiased measurements of underlying constructs across Italian and English versions. METHODS: Three constrained levels of measurement invariance were evaluated: configural invariance where equivalent numbers of factors/factor patterns were required; metric invariance where equivalent factor loadings were required; and scalar invariance where equivalent item intercepts between groups were required. Comparative fit index (CFI), root mean square error of approximation (RMSEA), and standardized root mean square residual (SRMR) fit indices and their changes between nested models were used to assess tenability of invariance constraints. RESULTS: Overall, the dataset included 3669 MS patients: 1605 (44%) Italian, mean age 41 years, 62% women, 69% with mild level of disability; 2064 (56%) English-speaking (840 [41%] from North America, 797 [39%] from Australasia, 427 [20%] from UK and Ireland), mean age 46 years, 83% women, 54% with mild level of disability. The configural invariance model showed acceptable fit (RMSEA = 0.052, CFI = 0.904, SRMR = 0.046); imposing loadings and intercepts equality constraints produced negligible worsening of fit (ΔRMSEA < 0.001, ΔCFI = - 0.002, ΔSRMR = 0.002 for metric invariance; ΔRMSEA = 0.003, ΔCFI = - 0.013, ΔSRMR = 0.003 for scalar invariance). CONCLUSIONS: These findings support measurement invariance of the MSQOL-54 across the two language versions, suggesting that the questionnaire has the same meaning and the same measurement paramaters in the Italian and English versions.

Italian validation of the caregiving tasks in multiple sclerosis scale (CTiMSS).

OBJECTIVES: Informal caregivers provide fundamental help to persons with multiple sclerosis through a variety of tasks ranging from practical assistance to psychological support. Caregiving Tasks in Multiple Sclerosis Scale (CTiMSS) is a reliable and valid measure assessing the complex structure of caregiving tasks within the context of multiple sclerosis. The present study was aimed to test the validity and reliability of the Italian translation of CTiMSS in a sample of informal caregivers of persons with multiple sclerosis. METHODS: A total of 580 caregivers (51.4% women, aged 18-81, M = 46.47, SD = 12.8) together with their care recipients (63.1% women, aged 19-60, M = 40.08, SD = 9.9) were involved in this study. Exploratory and confirmatory factor analyses with a split-sample approach were employed to evaluate construct validity. Convergent and discriminant validity were assessed using correlation indices with scales from Short Form Health Survey-36 and Positive and Negative Affect Schedule. Cronbach's alphas were used as a measure of reliability. RESULTS: Compared with the original CTiMSS 4-factor structure, a more stable and valid solution with 3 first-order factor loading on a single second-order factor was evaluated and confirmed; convergent and discriminant validity were also supported, and Cronbach's alpha values highlighted good-to-excellent reliability levels. CONCLUSION: Results supported the validity and reliability of the Italian CTiMSS. Thanks to its ability to assess specific caregiving tasks, the measure can be a useful instrument for tailoring intervention focused on the promotion of both caregivers' and care recipients' quality of life.

Correction to: Aging with multiple sclerosis: prevalence and profile of cognitive impairment.

The above article was published online with an error in author name's affiliation. The Author Claudia Niccolai has changed her affiliation to IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy.

Aging with multiple sclerosis: prevalence and profile of cognitive impairment.

BACKGROUND: The increase in life expectancy of patients with multiple sclerosis (MS) requires a better knowledge of disease features in the older patients group. OBJECTIVE: To describe the prevalence and profile of cognitive impairment (CI) in older patients with MS and perform a comparison with younger patients. METHODS: Patients were consecutively recruited for 6 months. Cognitive performance was assessed through the Brief Repeatable Battery and the Stroop Test. CI was defined as impairment in ≥ 2 cognitive domains. RESULTS: We identified 111 patients older than 55 years (mean age 59.7 years). The prevalence of CI was 77.4%, which was significantly higher than in younger patients (42.8%; p < 0.01). Information processing speed was the most impaired domain (68.8%), followed by verbal learning (49.5%), executive function (47.7%), and visuospatial learning (26.6%). We found no significant differences in the prevalence of impairment in the distinct cognitive domains between older and younger patients with CI. Depression and fatigue were not associated with increased CI among patients in the older age group (p > 0.70). CONCLUSION: There is a remarkably high frequency of CI in older patients with MS. The similar profile of CI between older and younger patients suggests that CI is mostly directly related to MS itself and not to comorbid age-related disorders.

Patients with paediatric-onset multiple sclerosis are at higher risk of cognitive impairment in adulthood: An Italian collaborative study.

BACKGROUND: Patients with paediatric-onset multiple sclerosis (POMS) could be at an increased risk for cognitive impairment (CI), given the potential harmful effects of disease activity in neurodevelopment. However, there is scarce information on their long-term cognitive outcomes. OBJECTIVE: To compare the prevalence and profile of CI between adults with a history of POMS and those with classic, adult-onset multiple sclerosis (AOMS). METHODS: Cognitive performance was assessed through the Brief Repeatable Battery (BRB) and the Stroop Test in consecutive patients referred to six Italian MS centres. CI was defined as impairment in ⩾2 cognitive domains. RESULTS: In all, 119 patients with POMS and 712 with AOMS were included in this analysis. The prevalence of CI was 48.0% in AOMS, 44.5% in POMS; with similar neuropsychological profile between the two groups. However, when adjusting for current age, we found a significantly increased risk for CI (odds ratio (OR) = 1.71; p = 0.02) and for impairment in information processing speed (OR = 1.86; p < 0.01) in patients with POMS. A higher Expanded Disability Status Scale (EDSS) was also identified in POMS ( p = 0.03) compared with AOMS patients. CONCLUSION: Patients with a history of POMS appear to be at higher risk of physical and cognitive disability than AOMS patients, after correcting for age effects, with particular involvement of information processing speed.

High prevalence of carriage of mcr-1-positive enteric bacteria among healthy children from rural communities in the Chaco region, Bolivia, September to October 2016.

BackgroundThe mcr-1 gene is a transferable resistance determinant against colistin, a last-resort antimicrobial for infections caused by multi-resistant Gram-negatives.AimTo study carriage of antibiotic-resistant bacteria in healthy school children as part of a helminth control and antimicrobial resistance survey in the Bolivian Chaco region.MethodsFrom September to October 2016 we collected faecal samples from healthy children in eight rural villages. Samples were screened for mcr-1- and mcr-2 genes. Antimicrobial susceptibility testing was performed, and a subset of 18 isolates representative of individuals from different villages was analysed by whole genome sequencing (WGS).ResultsWe included 337 children (mean age: 9.2 years, range: 7-11; 53% females). The proportion of mcr-1 carriers was high (38.3%) and present in all villages; only four children had previous antibiotic exposure. One or more mcr-1-positive isolates were recovered from 129 positive samples, yielding a total of 173 isolates (171 Escherichia coli, 1 Citrobacter europaeus, 1 Enterobacter hormaechei). No mcr-2 was detected. Co-resistance to other antimicrobials varied in mcr-positive E. coli. All 171 isolates were susceptible to carbapenems and tigecycline; 41 (24.0%) were extended-spectrum ß-lactamase producers and most of them (37/41) carried blaCTX-M-type genes. WGS revealed heterogeneity of clonal lineages and mcr-genetic supports.ConclusionThis high prevalence of mcr-1-like carriage, in absence of professional exposure, is unexpected. Its extent at the national level should be investigated with priority. Possible causes should be studied; they may include unrestricted use of colistin in veterinary medicine and animal breeding, and importation of mcr-1-positive bacteria via food and animals.

Age and disability drive cognitive impairment in multiple sclerosis across disease subtypes.

BACKGROUND: There is limited and inconsistent information on the clinical determinants of cognitive impairment (CI) in multiple sclerosis (MS). OBJECTIVE: The aim of this study was to compare the prevalence and profile of CI across MS disease subtypes and assess its clinical determinants. METHODS: Cognitive performance was assessed through the Brief Repeatable Battery and the Stroop test in consecutive patients with MS referred to six Italian centers. CI was defined as impairment in ⩾ 2 cognitive domains. RESULTS: A total of 1040 patients were included, 167 with clinically isolated syndrome (CIS), 759 with relapsing remitting (RR), 74 with secondary progressive (SP), and 40 with primary progressive (PP) disease course. The overall prevalence of CI was 46.3%; 34.5% in CIS, 44.5% in RR, 79.4% in SP, and 91.3% in PP. The severity of impairment and the number of involved domains were significantly higher in SP and primary progressive multiple sclerosis (PPMS) than in CIS and RR. In multivariable logistic regression analysis, the presence of CI was significantly associated with higher Expanded Disability Status Scale (EDSS) and older age. CONCLUSION: CI is present in all MS subtypes since the clinical onset and its frequency is increased in the progressive forms, but these differences seem to be more associated with patient age and physical disability than to disease subtype per se.

The cognitive reserve theory in the setting of pediatric-onset multiple sclerosis.

BACKGROUND: The study of cognitive reserve (CR) in relationship with cognitive impairment (CI) in pediatric-onset multiple sclerosis (POMS) may provide cues to identifying subjects at higher risk of impairment and scope for therapeutic strategies. OBJECTIVES: To assess the potential impact of CR on cognition in a cohort of POMS patients. METHODS: In all, 48 POMS patients were followed up for 4.7 ± 0.4 years. CI was defined as the failure of ⩾3 tests on an extensive neuropsychological battery. Change of neuropsychological performance was assessed through the Reliable Change Index (RCI) method. At baseline, CR was estimated by measuring the intelligence quotient (IQ). The relationships were assessed through multivariable regression analyses. RESULTS: At baseline, CI was detected in 14/48 (29.2%) patients. Two out of 57 healthy control (HC; 3.5%) met the same criteria of CI (p < 0.001). A deteriorating cognitive performance using the RCI method was observed in 18/48 patients (37.6%). Among the 34 cases who were cognitively preserved at baseline, a higher reserve predicted stable/improving performance (odds ratio (OR) = 1.11; 95% confidence interval (CI): 1.03-1.20; p = 0.006). CONCLUSION: Our results suggest that higher CR in POMS patients may protect from CI, particularly in subjects with initial cognitive preservation, providing relevant implications for counseling and rehabilitation strategies.

A comparison of the brief international cognitive assessment for multiple sclerosis and the brief repeatable battery in multiple sclerosis patients.

BACKGROUND: Recently, a Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) has been developed as an international and standardized brief cognitive test, which is easily performed in everyday clinical practice for neuropsychological assessment in multiple sclerosis (MS). However, we need to gather more information about this tool compared to other neuropsychological batteries. The aim of our study is to compare the performance of BICAMS and Brief Repeatable Battery (BRB) in MS subjects. METHODS: Tests of the BRB and BICAMS were administered to MS patients recruited from 11 Italian MS centres. Cognitive impairment (CI) was defined as the failure on at least two tests (scores below the fifth percentile) on the BRB and as the failure on at least one test of the BICAMS. The agreement between the performances on the two batteries was assessed through Cohen's K statistic. Finally we calculated the effects sizes for each test of the two batteries using Cohen's d. RESULTS: The two batteries were administered to 192 MS patients (142 women, 50 men; mean age 41.4 ± 10.8 years, mean education 12.3 ± 3.5 years). Mean scores of patients were lower compared to those of healthy subjects in all the cognitive measures examined. Forty-six MS patients were identified as impaired and 48 as unimpaired on both of the batteries, when the Symbol Digit Modalities Test (SDMT) was included in the analysis. Cohen's K statistic was 0.46 which corresponds to a moderate accord. If the SDMT was excluded from the BRB, 37 MS patients were identified as impaired and 57 as unimpaired on both of the batteries. Cohen's K statistic was 0.3 which corresponds to a poor accord. The SDMT, the Paced Auditory Serial Addition Test (PASAT) 3 and 2 yielded higher d values (SDMT 0.83, PASAT 3 0.65, PASAT 2 0.84). CONCLUSIONS: This study confirms the feasibility of BICAMS in everyday clinical practice for the identification of CI and highlights the good psychometric properties of the SDMT.

The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS): normative values with gender, age and education corrections in the Italian population.

BACKGROUND: BICAMS (Brief International Cognitive Assessment for Multiple Sclerosis) has been recently developed as brief, practical and universal assessment tool for cognitive impairment in MS subjects. It includes the Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test-2 (CVLT2) and the Brief Visuospatial Memory Test-Revised (BVMT-R) . In this study we aimed at gathering regression based normative data for the BICAMS battery in the Italian population. METHODS: Healthy subjects were consecutively recruited among patient friends and relatives. Corrections for demographics were calculated using multivariable linear regression models. Test-retest reliability was assessed using the Pearson correlation coefficient. RESULTS: The BICAMS battery was administered to 273 healthy subjects (180 women, mean age 38.9 ± 13.0 years, mean education 14.9 ± 3.0 years). Test-retest reliability was good for all the tests. CONCLUSIONS: The study provided normative data of the BICAMS for the Italian population confirming good test-retest reliability which can facilitate the use of the battery in clinical practice, also for longitudinal patient assessments.

Assessing executive function with the D-KEFS sorting test: normative data for a sample of the Italian adult population.

One of the major problems in clinical neuropsychology is to apply ecological, easily administrable and sensitive tests that can help in the diagnosis of executive functions. In the present paper we present normative values for the D-KEFS sorting test (ST), exploring the ability of reasoning, categorization abilities, problem solving, flexibility of thinking and abstraction. We collected normative data in a group of 181 normal Italian subjects aged between 20 and 69 years old, matched for educational level. Multiple regression analysis was performed to evaluate the potential effects of age, sex and education. Age and education had a significant effect on ST performance. Our study provided normative data for the D-KEFS ST for the adult Italian population, corrections of raw scores for relevant demographic factors, and percentile grids for both baseline data and on re-testing after 9 months of follow-up. These normative Italian values support the use of the D-KEFS ST as a valid instrument for initial neuropsychological evaluation and longitudinal analysis of executive functions in clinical practice and for research purposes.

Functional features of KPC-109, a novel 270-loop KPC-3 mutant mediating resistance to avibactam-based ß-lactamase inhibitor combinations and cefiderocol.

OBJECTIVES: To investigate a ceftazidime/avibactam (CZA)-resistant Klebsiella pneumoniae (NE368), isolated from a patient exposed to CZA, expressing a novel K. pneumoniae carbapenemase (KPC)-3 variant (KPC-109). METHODS: Antimicrobial susceptibility testing was performed by reference broth microdilution. Whole-genome sequencing (WGS) analysis of NE368 was performed combining a short- and long-reads approach (Illumina and Oxford Nanopore Technologies). Functional characterization of KPC-109 was performed to investigate the impact of KPC-109 production on the ß-lactam resistance phenotype of various Escherichia coli and Klebsiella pneumoniae strains, including derivatives of K. pneumoniae with OmpK35 and OmpK36 porin alterations. Horizontal transfer of the KPC-109-encoding plasmid was investigated by conjugation and transformation experiments. RESULTS: K. pneumoniae NE368 was isolated from a patient after repeated CZA exposure, and showed resistance to CZA, fluoroquinolones, piperacillin/tazobactam, expanded-spectrum cephalosporins, amikacin, carbapenems and cefiderocol. WGS revealed the presence of a large chimeric plasmid of original structure (pKPN-NE368), encoding a novel 270-loop mutated KPC-3 variant (KPC-109; ins_270_KYNKDD). KPC-109 production mediated resistance/decreased susceptibility to avibactam-based combinations (with ceftazidime, cefepime and aztreonam) and cefiderocol, with a trade-off on carbapenem resistance. However, in the presence of porin alterations commonly encountered in high-risk clonal lineages of K. pneumoniae, KPC-109 was also able to confer clinical-level resistance to carbapenems. Resistance of NE368 to cefiderocol was likely contributed by KPC-109 production acting in concert with a mutated EnvZ sensor kinase. The KPC-109-encoding plasmid did not appear to be conjugative. CONCLUSIONS: These findings expand current knowledge about the diversity of emerging KPC enzyme variants with 270-loop alterations that can be encountered in the clinical setting.