Cefepime versus carbapenems for treatment of AmpC beta-lactamase-producing Enterobacterales bloodstream infections.

PURPOSE: Cefepime is recommended for treating infections caused by AmpC beta-lactamase-producing Enterobacterales (AmpC-PE), though supporting evidence is limited. Therefore, this study compared outcomes associated with cefepime versus carbapenem therapy for bloodstream infections (BSIs) caused by AmpC-PE after phenotypic exclusion of ESBL-co-producing isolates. METHODS: This retrospective cohort study compared definite cefepime versus carbapenem treatment for AmpC-PE BSI in hospitalized patients of the University Hospital Basel, Switzerland, between 01/2015 and 07/2020. Primary outcomes included in-hospital death, renal impairment and neurologic adverse events; secondary outcomes included length of hospital stay and recurrent infection. RESULTS: Two hundred and seventy episodes of AmpC-PE BSI were included, 162, 77 and 31 were treated with a carbapenem, cefepime and other antibiotics, respectively. Patients treated with carbapenems were more likely to be transferred to the ICU on admission and more frequently had central venous catheter as a source of infection. In uni- and multivariable analyses, primary and secondary outcomes did not differ between the two treatment groups, except for more frequent occurrence of neurological adverse events among patients treated with carbapenems and shorter length of hospital stay among survivors treated with cefepime. CONCLUSION: After excluding isolates with phenotypic ESBL-co-production, cefepime was not associated with adverse outcomes compared to carbapenems when used to treat BSIs caused by AmpC-PE. Our study provides evidence to support the use of cefepime as a safe treatment strategy for AmpC-PE BSI, particularly in clinically stable patients without initial renal impairment or increased susceptibility to neurological adverse events.

Unsupervised machine learning predicts future sexual behaviour and sexually transmitted infections among HIV-positive men who have sex with men.

Machine learning is increasingly introduced into medical fields, yet there is limited evidence for its benefit over more commonly used statistical methods in epidemiological studies. We introduce an unsupervised machine learning framework for longitudinal features and evaluate it using sexual behaviour data from the last 20 years from over 3'700 participants in the Swiss HIV Cohort Study (SHCS). We use hierarchical clustering to find subgroups of men who have sex with men in the SHCS with similar sexual behaviour up to May 2017, and apply regression to test whether these clusters enhance predictions of sexual behaviour or sexually transmitted diseases (STIs) after May 2017 beyond what can be predicted with conventional parameters. We find that behavioural clusters enhance model performance according to likelihood ratio test, Akaike information criterion and area under the receiver operator characteristic curve for all outcomes studied, and according to Bayesian information criterion for five out of ten outcomes, with particularly good performance for predicting future sexual behaviour and recurrent STIs. We thus assess a methodology that can be used as an alternative means for creating exposure categories from longitudinal data in epidemiological models, and can contribute to the understanding of time-varying risk factors.

Decreasing Incidence and Determinants of Bacterial Pneumonia in People With HIV: The Swiss HIV Cohort Study.

BACKGROUND: Bacterial pneumonia is a leading reason for hospitalization among people with HIV (PWH); however, evidence regarding its drivers in the era of potent antiretroviral therapy is limited. METHODS: We assessed risk factors for bacterial pneumonia in the Swiss HIV Cohort Study using marginal models. We further assessed the relationship between risk factors and changes in bacterial pneumonia incidence using mediation analysis. RESULTS: We included 12927 PWH with follow-ups between 2008 and 2018. These patients had 985 bacterial pneumonia events during a follow-up of 100779 person-years. Bacterial pneumonia incidence significantly decreased from 13.2 cases/1000 person-years in 2008 to 6.8 cases/1000 person-years in 2018. Older age, lower education level, intravenous drug use, smoking, lower CD4-cell count, higher HIV load, and prior pneumonia were significantly associated with higher bacterial pneumonia incidence. Notably, CD4 cell counts 350-499 cells/µL were significantly associated with an increased risk compared to CD4 ≥ 500 cells/µL (adjusted hazard ratio, 1.39; 95% confidence interval, 1.01-1.89). Decreasing incidence over the last decade can be explained by increased CD4-cell counts and viral suppression and decreased smoking frequency. CONCLUSIONS: Improvements in cascade of care of HIV and decrease in smoking may have mediated a substantial decrease in bacterial pneumonia incidence.

A Possible Distinct Molecular Subtype (Quintuple-Wildtype) of Metastatic Colorectal Cancer in First-Line Anti-EGFR Therapy with Cetuximab Plus FOLFIRI - Palliative Precision Therapy and a Multidisciplinary Treatment Approach: Interim Analysis of the IVOPAK II Trial with Early Results.

OBJECTIVE: The study aimed to prospectively evaluate a new molecular biomarker panel (KRAS, NRAS, BRAF, PIK3CA, and ERBB2) for palliative first-line treatment of colorectal cancer (CRC), including a multidisciplinary treatment approach. The rate of secondary metastasis resections was assessed. PATIENTS AND METHODS: A total of 40 patients with definitively nonresectable metastatic CRC were enrolled from 10 centers before the interim analysis (June 2019) of the IVOPAK II trial (Interdisciplinary Care with Quality Control in Palliative Treatment of Colorectal Cancer). After determination of 5 molecular biomarkers in the tumor (KRAS, exons 2-4; NRAS, exons 2-4; BRAF V600E; PIK3CA; and ERBB2), patients in the IVOPAK II study received FOLFIRI plus cetuximab for all-RAS/quintuple-wildtype disease and FOLFIRI plus bevacizumab in the case of RAS mutations. The current article presents the early description of the clinical outcome of the interim analysis of IVOPAK II comparing the all-RAS/quintuple-wildtype and RAS-mutations populations, including a multidisciplinary-treated case report of a quintuple-wildtype patient. RESULTS: The quintuple-wildtype population treated with FOLFIRI plus cetuximab in first-line exhibited a significantly higher response rate and enhanced early tumor shrinkage in the interim analysis than the RAS-mutations population, as well as a high rate of secondary metastatic resections. CONCLUSION: Initial results of this new biomarker panel (quintuple-wildtype) are promising for anti-EGFR therapy with cetuximab plus doublet chemotherapy (FOLFIRI) in first-line treatment of metastatic CRC. These results warrant confirmation with higher case numbers in the IVOPAK II trial.

An MDS Evidence-Based Review on Treatments for Huntington's Disease.

BACKGROUND: Huntington's disease (HD) is a rare neurodegenerative disorder with protean clinical manifestations. Its management is challenging, consisting mainly of off-label treatments. OBJECTIVES: The International Parkinson and Movement Disorder Society commissioned a task force to review and evaluate the evidence of available therapies for HD gene expansion carriers. METHODS: We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Eligible randomized controlled trials were identified via an electronic search of the CENTRAL, MEDLINE, and EMBASE databases. All eligible trials that evaluated one or more of 33 predetermined clinical questions were included. Risk of bias was evaluated using the Cochrane Risk of Bias tool. A framework was adapted to allow for efficacy and safety conclusions to be drawn from the balance between the GRADE level of evidence and the importance of the benefit/harm of the intervention. RESULTS: Twenty-two eligible studies involving 17 interventions were included, providing data to address 8 clinical questions. These data supported a likely effect of deutetrabenazine on motor impairment, chorea, and dystonia and of tetrabenazine on chorea. The data did not support a disease-modifying effect for premanifest and manifest HD. There was no eligible evidence to support the use of specific treatments for depression, psychosis, irritability, apathy, or suicidality. Similarly, no evidence was eligible to support the use of physiotherapy, occupational therapy, exercise, dietary, or surgical treatments. CONCLUSIONS: Data for therapeutic interventions in HD are limited and support only the use of VMAT2 inhibitors for specific motor symptoms. © 2021 International Parkinson and Movement Disorder Society.

Assessing the drivers of syphilis among men who have sex with men in Switzerland reveals a key impact of screening frequency: A modelling study.

Over the last decade, syphilis diagnoses among men-who-have-sex-with-men (MSM) have strongly increased in Europe. Understanding the drivers of the ongoing epidemic may aid to curb transmissions. In order to identify the drivers of syphilis transmission in MSM in Switzerland between 2006 and 2017 as well as the effect of potential interventions, we set up an epidemiological model stratified by syphilis stage, HIV-diagnosis, and behavioral factors to account for syphilis infectiousness and risk for transmission. In the main model, we used 'reported non-steady partners' (nsP) as the main proxy for sexual risk. We parameterized the model using data from the Swiss HIV Cohort Study, Swiss Voluntary Counselling and Testing center, cross-sectional surveys among the Swiss MSM population, and published syphilis notifications from the Federal Office of Public Health. The main model reproduced the increase in syphilis diagnoses from 168 cases in 2006 to 418 cases in 2017. It estimated that between 2006 and 2017, MSM with HIV diagnosis had 45.9 times the median syphilis incidence of MSM without HIV diagnosis. Defining risk as condomless anal intercourse with nsP decreased model accuracy (sum of squared weighted residuals, 378.8 vs. 148.3). Counterfactual scenarios suggested that increasing screening of MSM without HIV diagnosis and with nsP from once every two years to twice per year may reduce syphilis incidence (at most 12.8% reduction by 2017). Whereas, increasing screening among MSM with HIV diagnosis and with nsP from once per year to twice per year may substantially reduce syphilis incidence over time (at least 63.5% reduction by 2017). The model suggests that reporting nsP regardless of condom use is suitable for risk stratification when modelling syphilis transmission. More frequent screening of MSM with HIV diagnosis, particularly those with nsP may aid to curb syphilis transmission.

Mitochondrial organization and structure are compromised in fibroblasts from patients with Huntington's disease.

Huntington´s disease (HD) is a progressive neurodegenerative disease with onset in adulthood that leads to a complete disability and death in approximately 20 years after onset of symptoms. HD is caused by an expansion of a CAG triplet in the gene for huntingtin. Although the disease causes most damage to striatal neurons, other parts of the nervous system and many peripheral tissues are also markedly affected. Besides huntingtin malfunction, mitochondrial impairment has been previously described as an important player in HD. This study focuses on mitochondrial structure and function in cultivated skin fibroblasts from 10 HD patients to demonstrate mitochondrial impairment in extra-neuronal tissue. Mitochondrial structure, mitochondrial fission, and cristae organization were significantly disrupted and signs of elevated apoptosis were found. In accordance with structural changes, we also found indicators of functional alteration of mitochondria. Mitochondrial disturbances presented in fibroblasts from HD patients confirm that the energy metabolism damage in HD is not localized only to the central nervous system, but also may play role in the pathogenesis of HD in peripheral tissues. Skin fibroblasts can thus serve as a suitable cellular model to make insight into HD pathobiochemical processes and for the identification of possible targets for new therapies.

Cohort-Derived Machine Learning Models for Individual Prediction of Chronic Kidney Disease in People Living With Human Immunodeficiency Virus: A Prospective Multicenter Cohort Study.

BACKGROUND: It is unclear whether data-driven machine learning models, which are trained on large epidemiological cohorts, may improve prediction of comorbidities in people living with human immunodeficiency virus (HIV). METHODS: In this proof-of-concept study, we included people living with HIV in the prospective Swiss HIV Cohort Study with a first estimated glomerular filtration rate (eGFR) >60 mL/minute/1.73 m2 after 1 January 2002. Our primary outcome was chronic kidney disease (CKD)-defined as confirmed decrease in eGFR ≤60 mL/minute/1.73 m2 over 3 months apart. We split the cohort data into a training set (80%), validation set (10%), and test set (10%), stratified for CKD status and follow-up length. RESULTS: Of 12 761 eligible individuals (median baseline eGFR, 103 mL/minute/1.73 m2), 1192 (9%) developed a CKD after a median of 8 years. We used 64 static and 502 time-changing variables: Across prediction horizons and algorithms and in contrast to expert-based standard models, most machine learning models achieved state-of-the-art predictive performances with areas under the receiver operating characteristic curve and precision recall curve ranging from 0.926 to 0.996 and from 0.631 to 0.956, respectively. CONCLUSIONS: In people living with HIV, we observed state-of-the-art performances in forecasting individual CKD onsets with different machine learning algorithms.

Telomere Length, Traditional Risk Factors, Factors Related to Human Immunodeficiency Virus (HIV) and Coronary Artery Disease Events in Swiss Persons Living With HIV.

BACKGROUND: Leukocyte telomere length (TL) shortens with age and is associated with coronary artery disease (CAD) events in the general population. Persons living with human immunodeficiency virus (HIV; PLWH) may have accelerated atherosclerosis and shorter TL than the general population. It is unknown whether TL is associated with CAD in PLWH. METHODS: We measured TL by quantitative polymerase chain reaction (PCR) in white Swiss HIV Cohort Study participants. Cases had a first CAD event during 1 January 2000 to 31 December 2017. We matched 1-3 PLWH controls without CAD events on sex, age, and observation time. We obtained univariable and multivariable odds ratios (OR) for CAD from conditional logistic regression analyses. RESULTS: We included 333 cases (median age 54 years; 14% women; 83% with suppressed HIV RNA) and 745 controls. Median time (interquartile range) of TL measurement was 9.4 (5.9-13.8) years prior to CAD event. Compared to the 1st (shortest) TL quintile, participants in the 5th (longest) TL quintile had univariable and multivariable CAD event OR = 0.56 (95% confidence interval [CI], .35-.91) and OR = 0.54 (95% CI, .31-.96). Multivariable OR for current smoking was 1.93 (95% CI, 1.27-2.92), dyslipidemia OR = 1.92 (95% CI, 1.41-2.63), and for recent abacavir, cumulative lopinavir, indinavir, and darunavir exposure was OR = 1.82 (95% CI, 1.27-2.59), OR = 2.02 (95% CI, 1.34-3.04), OR = 3.42 (95% CI, 2.14-5.45), and OR = 1.66 (95% CI, 1.00-2.74), respectively. The TL-CAD association remained significant when adjusting only for Framingham risk score, when excluding TL outliers, and when adjusting for CMV-seropositivity, HCV-seropositivity, time spent with detectable HIV viremia, and injection drug use. CONCLUSIONS: In PLWH, TL measured >9 years before, is independently associated with CAD events after adjusting for multiple traditional and HIV-related factors.

Antimicrobial Prophylaxis for Postoperative Urinary Tract Infections in Transurethral Resection of Bladder Tumors: A Systematic Review and Meta-Analysis.

PURPOSE: The administration of antimicrobial prophylaxis for postoperative urinary tract infections following transurethral resection of bladder tumors is controversial. We aimed to systematically review evidence on the potential effect of antimicrobial prophylaxis on postoperative urinary tract infections and asymptomatic bacteriuria. MATERIALS AND METHODS: We conducted a systematic search in Embase®, Medline® and the Cochrane Central Register of Controlled Trials. Randomized controlled trials and nonrandomized controlled trials assessing the effect of any form of antimicrobial prophylaxis in patients with transurethral resection of bladder tumors on postoperative urinary tract infections or asymptomatic bacteriuria were included. Risk of bias was assessed using RoB 2.0 or the Newcastle-Ottawa Scale. Fixed and random effects meta-analyses were conducted. As a potential basis for a scoping review, we exploratorily searched Medline for risk factors for urinary tract infections after transurethral resection of bladder tumors. The protocol was registered on PROSPERO (CRD42019131733). RESULTS: Of 986 screened publications, 7 studies with 1,725 participants were included; the reported effect sizes varied considerably. We found no significant effect of antimicrobial prophylaxis on urinary tract infections: the pooled odds ratio of the random effects model was 1.55 (95% CI 0.73-3.31). The random effects meta-analysis examining the effect of antimicrobial prophylaxis on asymptomatic bacteriuria showed an OR of 0.43 (0.18-1.04). Risk of bias was moderate. Our exploratory search identified 3 studies reporting age, preoperative pelvic radiation, preoperative hospital stay, duration of operation, tumor size, preoperative asymptomatic bacteriuria and pyuria as risk factors for urinary tract infections following transurethral resection of bladder tumors. CONCLUSIONS: We observed insufficient evidence supporting routine antimicrobial prophylaxis in patients undergoing transurethral resection of bladder tumors for the prevention of postoperative urinary tract infections; our findings may inform harmonization of international guidelines.

High incidence of urinary tract infections after photoselective laser vaporisation of the prostate: a risk factor analysis of 665 patients.

PURPOSE: Although photoselective laser vaporisation of the prostate (PVP) is a recognised alternative to transurethral resection in treating benign prostatic obstruction, there is limited data on the incidence and determinants of postoperative urinary tract infections (UTI). We assessed patients subjected to PVP, evaluating incidence and potential determinants of postoperative UTIs. MATERIALS AND METHODS: Consecutive patients undergoing PVP between April 2010 and August 2018 were candidates for this retrospective cohort study. The primary outcome measure was microbiologically confirmed postoperative UTI. We fitted uni- and multi-variable Cox models to identify potential risk factors. RESULTS: Among the 665 included patients, 20% developed postoperative UTIs. The overall incidence rate per 100 patient-days was 0.65 (95% confidence interval [CI] 0.55-0.77). Risk factors for postoperative UTIs were end-stage renal failure (adjusted hazard ratio [aHR] = 14.10, 95% CI 2.08-64.58; p = 0.001) and presence of at least one of the following factors in the 3 months preceding PVP: (i) placement of urinary catheter, (ii) bacteriuria, (iii) UTI, or (iv) antimicrobial treatment (composite aHR = 1.99, 95% CI 1.22-3.24; p < 0.001). There was no apparent association between choice or duration of antimicrobial prophylaxis and incident UTIs. CONCLUSIONS: Our analysis revealed a high incidence of UTIs after PVP and served to identify certain preoperative risk factors. Neither the choice of antimicrobial regimen nor its duration affected the incidence of UTIs. Prolonged antimicrobials proved to be disproportionately high, warranting further scrutiny in randomised controlled trials.

Frequent Door Openings During Cardiac Surgery Are Associated With Increased Risk for Surgical Site Infection: A Prospective Observational Study.

BACKGROUND: Preliminary studies that analyzed surrogate markers have suggested that operating room (OR) door openings may be a risk factor for surgical site infection (SSI). We therefore aimed to estimate the effect of OR door openings on SSI risk in patients undergoing cardiac surgery. METHODS: This prospective, observational study involved consecutive patients undergoing cardiac surgery in 2 prespecified ORs equipped with automatic door-counting devices from June 2016 to October 2017. Occurrence of an SSI within 30 days after cardiac surgery was our primary outcome measure. Respective outcome data were obtained from a national SSI surveillance cohort. We analyzed the relationship between mean OR door opening frequencies and SSI risk by use of uni- and multivariable Cox regression models. RESULTS: A total of 301 594 OR door openings were recorded during the study period, with 87 676 eligible door openings being logged between incision and skin closure. There were 688 patients included in the study, of whom 24 (3.5%) developed an SSI within 30 days after surgery. In uni- and multivariable analysis, an increased mean door opening frequency during cardiac surgery was associated with higher risk for consecutive SSI (adjusted hazard ratio per 5-unit increment, 1.49; 95% confidence interval, 1.11-2.00; P = .008). The observed effect was driven by internal OR door openings toward the clean instrument preparation room. CONCLUSIONS: Frequent door openings during cardiac surgery were independently associated with an increased risk for SSI. This finding warrants further study to establish a potentially causal relationship between OR door openings and the occurrence of SSI.

Early versus late onset bloodstream infection during neutropenia after high-dose chemotherapy for hematologic malignancy.

PURPOSE: The length of neutropenia has a significant impact on the incidence of bloodstream infection (BSI) in cancer patients, but limited information is available about the pathogen distribution in late BSI. METHODS: Between 2002 and 2014, BSI episodes in patients with neutropenia receiving chemotherapy for hematologic malignancies were prospectively identified by multicenter, active surveillance in Germany, Switzerland and Austria. The incidence of first BSI episodes, their microbiology and time to BSI onset during the first episode of neutropenia of 15,988 patients are described. RESULTS: The incidence rate of BSI episodes was 14.7, 8.7, and 4.7 per 1000 patient-days in the first, second, and third week of neutropenia, respectively. BSI developed after a median of 5 days of neutropenia (interquartile range [IQR] 3-10 days). The medium duration of neutropenia to BSI onset was 4 days in Escherichia coli (IQR 3-7 days), Klebsiella spp. (2-8 days), and Staphylococcus aureus (3-6 days). In contrast, BSI due to Enterococcus faecium occurred after a median of 9 days (IQR 6-14 days; p < 0.001 vs. other BSI). Late onset of BSI (occurring after the first week of neutropenia) was also observed for Stenotrophomonas maltophilia (12 days, IQR 7-17 days; p < 0.001), and non-albicans Candida spp. (13 days, IQR 8-19 days; p < 0.001). CONCLUSIONS: Over the course of neutropenia, the proportion of difficult to treat pathogens such as E. faecium, S. maltophilia, and Candida spp. increased. Among other factors, prior duration of neutropenia may help to guide empiric antimicrobial treatment in febrile neutropenia.

Contribution of specific pathogens to bloodstream infection mortality in neutropenic patients with hematologic malignancies: Results from a multicentric surveillance cohort study.

Bloodstream infection (BSI) remains a serious complication in patients with hematologic malignancies and neutropenia. The risk factors for mortality after BSI and the contributions of BSI pathogens to mortality remain incompletely understood. We evaluated first BSI among adult neutropenic patients undergoing high-dose chemotherapy for hematologic malignancies in the setting of (a) an early disease stage of autologous (auto-HSCT) or allogeneic (allo-HSCT) hematopoietic stem cell transplantation or (b) for acute leukemia. Risk factors for intensive care admission and all-cause mortality were analyzed by multivariable logistic regression 7 and 30 days after onset of the first BSI in the first neutropenic episode. Between 2002 and 2015, 9080 patients met the study inclusion criteria, and 1424 (16%) developed BSIs, most of them during the first week of neutropenia. Mortality during neutropenia within 7 days and 30 days after BSI onset was 2.5% and 5.1%, respectively, and differed considerably between BSI pathogens. Both 7-day and 30-day mortalities were highest for Pseudomonas aeruginosa BSI (16.7% and 26.7%, respectively) and lowest for BSI due to coagulase-negative Staphylococcus spp. (CoNS) and Streptococcus spp. BSI pathogens were independently associated with 7-day mortality included P aeruginosa, Klebsiella spp., Enterobacter spp., Serratia spp., and enterococci. Only gram-negative BSI and candidemia were associated with admission to intensive care within 7 days after BSI onset. BSI caused by P aeruginosa continues to carry a particularly poor prognosis in neutropenic patients. The unexpected association between enterococcal BSI and increased mortality needs further study.

Mitochondrial membrane protein-associated neurodegeneration: a case report and literature review.

Mitochondrial membrane protein-associated neurodegeneration (MPAN) is an autosomal recessive disorder caused by mutation in the C19orf12 gene. We report a compound heterozygous c.[32C>T];[205G>A;424A>G] (p.[Thr11Met];[Gly69Arg;Lys142Glu]) Czech patient who manifested with right foot dystonia, impaired handwriting, attention deficit, and signs of iron accumulation on brain MRI. Gradually, he developed dysarthria, spastic-dystonic gait, pedes cavi, and atrophy of leg muscles. Additionally, we report demographic parameters, clinical signs, and allelic frequencies of C19orf12 mutations of all published MPAN cases. We compared the most frequent mutations, p.Thr11Met and p.Gly69ArgfsX10; the latter was associated with younger age at onset and more frequent optic atrophy in homozygotes.

Molecular diversity of combined and complex dystonia: insights from diagnostic exome sequencing.

Combined and complex dystonias are heterogeneous movement disorders combining dystonia with other motor and/or systemic signs. Although we are beginning to understand the diverse molecular causes of these disease entities, clinical pattern recognition and conventional genetic workup achieve an etiological diagnosis only in a minority of cases. Our goal was to provide a window into the variable genetic origins and distinct clinical patterns of combined/complex dystonia more broadly. Between August 2016 and January 2017, we applied whole-exome sequencing to a cohort of nine patients with varied combined and/or complex dystonic presentations, being on a diagnostic odyssey. Bioinformatics analyses, co-segregation studies, and sequence-interpretation algorithms were employed to detect causative mutations. Comprehensive clinical review was undertaken to define the phenotypic spectra and optimal management strategies. On average, we observed a delay in diagnosis of 23 years before whole-exome analysis enabled determination of each patient's genetic defect. Whereas mutations in ACTB, ATP1A3, ADCY5, and SGCE were associated with particular phenotypic clues, trait manifestations arising from mutations in PINK1, MRE11A, KMT2B, ATM, and SLC6A1 were different from those previously reported in association with these genes. Apart from improving counseling for our entire cohort, genetic findings had actionable consequences on preventative measures and therapeutic interventions for five patients. Our investigation confirms unique genetic diagnoses, highlights key clinical features and phenotypic expansions, and suggests whole-exome sequencing as a first-tier diagnostic for combined/complex dystonia. These results might stimulate independent teams to extend the scope of agnostic genetic screening to this particular phenotypic group that remains poorly characterized through existing studies.

KMT2B rare missense variants in generalized dystonia.

BACKGROUND: Recently a novel syndrome of childhood-onset generalized dystonia originating from mutations in lysine-specific methyltransferase 2B (KMT2B) has been reported. METHODS: We sequenced the exomes of 4 generalized dystonia-affected probands recruited from a Prague movement disorders center (Czech Republic). Bioinformatics analyses were conducted to select candidate causal variants in described dystonia-mutated genes. After cosegregation testing, checklists from the American College of Medical Genetics and Genomics were adopted to judge variant pathogenicity. RESULTS: Three novel, predicted protein-damaging missense variants in KMT2B were identified (p.Glu1234Lys, p.Ala1541Val, p.Arg1779Gln). Meeting pathogenicity criteria, p.Glu1234Lys was absent from population-based controls, situated in a key protein domain, and had occurred de novo. The associated phenotype comprised adolescence-onset generalized isolated dystonia with prominent speech impairment. Although linked to a similar clinical expression, p.Ala1541Val and p.Arg1779Gln remained of uncertain significance. CONCLUSIONS: Rare missense variation in KMT2B represents an additional cause of generalized dystonia. Application of sequence interpretation standards is required before assigning pathogenicity to a KMT2B missense variant. © 2017 International Parkinson and Movement Disorder Society.

Motion and emotion: anxiety-axial connections in Parkinson's disease.

Anxiety is a serious and frequent complication in Parkinson's disease (PD) that significantly affects the quality of life of patients. Multiple neuroanatomical, experimental, and clinical studies suggest its close association with axial disturbances. However, whether this relation applies for PD patients (commonly suffering from axial difficulties, such as balance and gait disturbance) has not been properly tested yet. The purpose of this study was to determine whether PD patients suffering from axial symptoms have higher levels of anxiety than others and to identify other factors associated with anxiety-axial connections. In this questionnaire study, 212 patients with PD were assessed by standardized scales, such as Hamilton Anxiety Scale, Montgomery-Asberg Depression Rating Scale, Montreal Cognitive Assessment, examining their mood and cognitive status. These data were correlated to dominant motor symptoms of these patients, such as tremor, rigidity, bradykinesia, and axial symptoms. Unlike other motor symptoms, only axial symptoms showed to be significantly related to higher levels of anxiety. The patients suffering from anxiety and axial problems have also shown significantly higher depression levels. Axial disturbances are related to higher anxiety levels in PD patients. It is crucial to pay high attention to symptoms of anxiety in patients having postural instability or gait disorder. Further clinical studies are desirable to investigate new, practical implications of anxiety-axial connection to provide complex management options of these serious symptoms.

Frontal Assessment Battery in Parkinson's Disease: Validity and Morphological Correlates.

OBJECTIVES: Executive dysfunction is a common feature in Parkinson's disease (PD). However, there is a lack of brief validated instruments for executive dysfunction in PD. METHODS: The aim of the present study was to assess the relation of Frontal Assessment Battery (FAB) scores to age and education, to verify the utility of FAB in the evaluation of executive dysfunction in PD and to differentiate between controls (n=41), PD patients with normal cognition (PD-NC; n=41; Hoehn and Yahr stages 2-3) and PD with mild cognitive impairment (PD-MCI; n=32; Hoehn and Yahr stages 2-3). In addition, we studied the relation between voxel-based morphometric (VBM) data and FAB results in PD. RESULTS: We found that FAB scores are significantly related to age and education. The FAB has shown discriminative validity for the differentiation of PD-MCI from PD-NC and controls (area under the curve >.80). Also, the VBM analysis revealed lower FAB scores are specifically related to lower gray matter density in the right ventromedial prefrontal areas and precuneus. CONCLUSIONS: The FAB can be recommended as a valid instrument for PD-MCI Level I screening. FAB is sensitive to frontal lobe involvement in PD as reflected by lower gray matter density in prefrontal areas. (JINS, 2017, 23, 675-684).