Reliability, construct and concurrent validity of a smartphone-based cognition test in multiple sclerosis.

BACKGROUND: Early detection and monitoring of cognitive dysfunction in multiple sclerosis (MS) may be enabled with smartphone-adapted tests that allow frequent measurements in the everyday environment. OBJECTIVES: The aim of this study was to determine the reliability, construct and concurrent validity of a smartphone-adapted Symbol Digit Modalities Test (sSDMT). METHODS: During a 28-day follow-up, 102 patients with MS and 24 healthy controls (HC) used the MS sherpa® app to perform the sSDMT every 3 days on their own smartphone. Patients performed the Brief International Cognitive Assessment for MS at baseline. Test-retest reliability (intraclass correlation coefficients, ICC), construct validity (group analyses between cognitively impaired (CI), cognitively preserved (CP) and HC for differences) and concurrent validity (correlation coefficients) were assessed. RESULTS: Patients with MS and HC completed an average of 23.2 (SD = 10.0) and 18.3 (SD = 10.2) sSDMT, respectively. sSDMT demonstrated high test-retest reliability (ICCs > 0.8) with a smallest detectable change of 7 points. sSDMT scores were different between CI patients, CP patients and HC (all ps < 0.05). sSDMT correlated modestly with the clinical SDMT (highest r = 0.690), verbal (highest r = 0.516) and visuospatial memory (highest r = 0.599). CONCLUSION: Self-administered smartphone-adapted SDMT scores were reliable and different between patients who were CI, CP and HC and demonstrated concurrent validity in assessing information processing speed.

Performance validity in outpatients with multiple sclerosis and cognitive complaints.

BACKGROUND: Suboptimal performance during neuropsychological assessment renders cognitive test results invalid. However, suboptimal performance has rarely been investigated in multiple sclerosis (MS). OBJECTIVES: To investigate potential underlying mechanisms of suboptimal performance in MS. METHODS: Performance validity testing, neuropsychological assessments, neuroimaging, and questionnaires were analyzed in 99 MS outpatients with cognitive complaints. Based on performance validity testing patients were classified as valid or invalid performers, and based on neuropsychological test results as cognitively impaired or preserved. Group comparisons and correlational analyses were performed on demographics, patient-reported, and disease-related outcomes. RESULTS: Twenty percent displayed invalid performance. Invalid and valid performers did not differ regarding demographic, patient-reported, and disease-related outcomes. Disease severity of invalid and valid performers with cognitive impairment was comparable, but worse than cognitively preserved valid performers. Lower performance validity scores related to lower cognitive functioning, lower education, being male, and higher disability levels (p < 0.05). CONCLUSION: Suboptimal performance frequently occurs in patients with MS and cognitive complaints. In both clinical practice and in cognitive research, suboptimal performance should be considered in the interpretation of cognitive outcomes. Identification of factors that differentiate between suboptimal and optimal performers with cognitive impairment needs further exploration.

Thin-Layer-Agar-Based Direct Phenotypic Drug Susceptibility Testing on Sputum in Eswatini Rapidly Detects Mycobacterium tuberculosis Growth and Rifampicin Resistance Otherwise Missed by WHO-Endorsed Diagnostic Tests.

Xpert MTB/RIF rapidly detects resistance to rifampicin (RR); however, this test misses I491F-RR conferring rpoB mutation, common in southern Africa. In addition, Xpert MTB/RIF does not distinguish between viable and dead Mycobacterium tuberculosis (MTB). We aimed to investigate the ability of thin-layer agar (TLA) direct drug-susceptibility testing (DST) to detect MTB and its drug-resistance profiles in field conditions in Eswatini. Consecutive samples were tested in parallel with Xpert MTB/RIF and TLA for rifampicin (1.0 µg/ml) and ofloxacin (2.0 µg/ml). TLA results were compared at the Reference Laboratory in Antwerp with indirect-DST on Löwenstein-Jensen or 7H11 solid media and additional phenotypic and genotypic testing to resolve discordance. TLA showed a positivity rate for MTB detection of 7.1% versus 10.0% for Xpert MTB/RIF. Of a total of 4,547 samples included in the study, 200 isolates were available for comparison to the composite reference. Within a median of 18.4 days, TLA detected RR with 93.0% sensitivity (95% confidence interval [CI], 77.4 to 98.0) and 99.4% specificity (95% CI, 96.7 to 99.9) versus 62.5% (95% CI, 42.7 to 78.8) and 99.3% (95% CI, 96.2 to 99.9) for Xpert MTB/RIF. Eight isolates, 28.6% of all RR-confirmed isolates, carried the I491F mutation, all detected by TLA. TLA also correctly identified 183 of the 184 ofloxacin-susceptible isolates (99.5% specificity; 95% CI, 97.0 to 99.9). In field conditions, TLA rapidly detects RR, and in this specific setting, it contributed to detection of additional RR patients over Xpert MTB/RIF, mainly but not exclusively due to I491F. TLA also accurately excluded fluoroquinolone resistance.

Neuroprotective effects of exercise in people with progressive multiple sclerosis (Exercise PRO-MS): study protocol of a phase II trial.

BACKGROUND: Neurodegeneration, rather than inflammation, plays a key role in the progressive phase of multiple sclerosis (MS). Current disease modifying treatment options for people with progressive MS (PMS) do not specifically target neurodegeneration. Preliminary evidence suggests that exercise therapy might have neuroprotective effects. However, neuroprotective effect studies of exercise interventions in PMS are scarce and the possible mode of action underlying neuroprotective effects of exercise are unknown and need to be elucidated. The main aim of this phase II trial is to assess whether progressive resistance training (PRT) and high intensity interval training (HIIT), can slow down neurodegeneration in people with PMS. METHODS: In a single-blinded phase II clinical trial with an extended baseline period, 60 people with PMS will be randomly assigned to PRT or HIIT. The participants should have had a relapse onset of MS with confirmed disease progression, however still ambulatory. The duration of the study is 48 weeks, consisting of 16 weeks baseline period (no intervention), 16 weeks intervention and 16 weeks follow-up. Patient-tailored training will be performed 3 times per week for one hour in groups, led by an experienced physiotherapist. The primary outcome measure is neurodegeneration, measured as whole brain atrophy on magnetic resonance imaging (MRI). Secondary outcome parameters will include other biomarkers associated with neurodegeneration (i.e. regional brain atrophy, lesion load, white matter integrity, resting state functional connectivity, blood biomarkers (brain derived neurotrophic factor (BDNF) and serum neurofilament light (sNFL)), patient functioning (physical and cognitive) and cardiovascular risk factors. DISCUSSION: Besides the primary outcome measures, this study will examine a large variety of biomarkers associated with neurodegeneration after an exercise intervention. Combining outcome parameters may help to elucidate the mode of action underlying neuroprotective effects of exercise. TRIAL REGISTRATION: This trial is prospectively registered at the Dutch Trial Registry (number NL8265, date 06-01-2020).

Molecular Biomarkers for Celiac Disease: Past, Present and Future.

Celiac disease (CeD) is a complex immune-mediated disorder that is triggered by dietary gluten in genetically predisposed individuals. CeD is characterized by inflammation and villous atrophy of the small intestine, which can lead to gastrointestinal complaints, malnutrition, and malignancies. Currently, diagnosis of CeD relies on serology (antibodies against transglutaminase and endomysium) and small-intestinal biopsies. Since small-intestinal biopsies require invasive upper-endoscopy, and serology cannot predict CeD in an early stage or be used for monitoring disease after initiation of a gluten-free diet, the search for non-invasive biomarkers is ongoing. Here, we summarize current and up-and-coming non-invasive biomarkers that may be able to predict, diagnose, and monitor the progression of CeD. We further discuss how current and emerging techniques, such as (single-cell) transcriptomics and genomics, can be used to uncover the pathophysiology of CeD and identify non-invasive biomarkers.

Multi-country outbreak of Salmonella enteritidis infection linked to the international ice hockey tournament.

In April 2015, Finnish public health authorities alerted European Union member states of a possible multi-country Salmonella enteritidis outbreak linked to an international youth ice-hockey tournament in Latvia. The European Centre for Disease Prevention and Control (ECDC), Finnish and Latvian authorities initiated an outbreak investigation to identify the source. The investigation included a description of the outbreak, retrospective cohort study, microbiological investigation and trace-back. We identified 154 suspected and 96 confirmed cases from seven countries. Consuming Bolognese sauce and salad at a specific event arena significantly increased the risk of illness. Isolates from Finnish, Swedish and Norwegian cases had an identical multiple-locus variable-number of tandem repeats analysis-profile (3-10-6-4-1). Breaches in hygiene and food storing practices in the specific arena's kitchen allowing for cross-contamination were identified. Riga Cup participants were recommended to follow good hand hygiene and consume only freshly cooked foods. This investigation demonstrated that the use of ECDC's Epidemic Intelligence Information System for Food- and Waterborne Diseases and Zoonoses platform was essential to progress the investigation by facilitating information exchange between countries. Cross-border data sharing to perform whole genome sequencing gave relevant information regarding the source of the outbreak.

Specific gyrA gene mutations predict poor treatment outcome in MDR-TB.

OBJECTIVES: Mutations in the gyrase genes cause fluoroquinolone resistance in Mycobacterium tuberculosis. However, the predictive value of these markers for clinical outcomes in patients with MDR-TB is unknown to date. The objective of this study was to determine molecular markers and breakpoints predicting second-line treatment outcomes in M. tuberculosis patients treated with fourth-generation fluoroquinolones. METHODS: We analysed treatment outcome data in relation to the gyrA and gyrB sequences and MICs of ofloxacin, gatifloxacin and moxifloxacin for pretreatment M. tuberculosis isolates from 181 MDR-TB patients in Bangladesh whose isolates were susceptible to injectable drugs. RESULTS: The gyrA 90Val, 94Gly and 94Ala mutations were most frequent, with the highest resistance levels for 94Gly mutants. Increased pretreatment resistance levels (>2 mg/L), related to specific mutations, were associated with lower cure percentages, with no cure in patients whose isolates were resistant to gatifloxacin at 4 mg/L. Any gyrA 94 mutation, except 94Ala, predicted a significantly lower proportion of cure compared with all other gyrA mutations taken together (all non-94 mutants + 94Ala) [OR = 4.3 (95% CI 1.4-13.0)]. The difference in treatment outcome was not explained by resistance to the other drugs. CONCLUSIONS: Our study suggests that gyrA mutations at position 94, other than Ala, predict high-level resistance to gatifloxacin and moxifloxacin, as well as poor treatment outcome, in MDR-TB patients in whom an injectable agent is still effective.

Tuberculosis drug resistance in Bamako, Mali, from 2006 to 2014.

BACKGROUND: Although Drug resistance tuberculosis is not a new phenomenon, Mali remains one of the "blank" countries without systematic data. METHODS: Between 2006 and 2014, we enrolled pulmonary TB patients from local TB diagnostics centers and a university referral hospital in several observational cohort studies. These consecutive patients had first line drug susceptibility testing (DST) performed on their isolates. A subset of MDR was subsequently tested for second line drug resistance. RESULTS: A total of 1186 mycobacterial cultures were performed on samples from 522 patients, including 1105 sputa and 81 blood samples, yielding one or more Mycobacterium tuberculosis complex (Mtbc) positive cultures for 343 patients. Phenotypic DST was performed on 337 (98.3%) unique Mtbc isolates, of which 127 (37.7%) were resistant to at least one drug, including 75 (22.3%) with multidrug resistance (MDR). The overall prevalence of MDR-TB was 3.4% among new patients and 66.3% among retreatment patients. Second line DST was available for 38 (50.7%) of MDR patients and seven (18.4%) had resistance to either fluoroquinolones or second-line injectable drugs. CONCLUSION: The drug resistance levels, including MDR, found in this study are relatively high, likely related to the selected referral population. While worrisome, the numbers remained stable over the study period. These findings prompt a nationwide drug resistance survey, as well as continuous surveillance of all retreatment patients, which will provide more accurate results on countrywide drug resistance rates and ensure that MDR patients access appropriate second line treatment.

Event-based surveillance of food- and waterborne diseases in Europe: urgent inquiries (outbreak alerts) during 2008 to 2013.

During 2008 to 2013, 215 outbreak alerts, also known as 'urgent inquiries' (UI), for food- and waterborne diseases were launched in Europe, the majority of them (135; 63%) being related to salmonellosis. For 110 (51%) UI, a potential food vehicle of infection was identified, with vegetables being the most reported category (34;31%). A total of 28% (n = 60) of the outbreaks reported had an international dimension, involving at least two countries (mean: 4; standard deviation: 2; range:2­14). Participating countries posted 2,343 messages(initial posts and replies, excluding updates), with a median of 11 messages per urgent inquiry (range:1­28). Of 60 multicountry UI, 50 involved between two and four countries. The UI allowed early detection of multicountry outbreaks, facilitated the identification of the suspected vehicles and consequently contributed to the timely implementation of control measures. The introduction of an epidemic intelligence information system platform in 2010 has strengthened the role of the Food- and Waterborne Diseases and Zoonoses network in facilitating timely exchange of information between public health authorities of the participating countries.

Influence of personalized extended interval dosing on the natalizumab wearing-off effect - a sub-study of the NEXT-MS trial.

BACKGROUND AND OBJECTIVES: Wearing-off symptoms during natalizumab treatment in multiple sclerosis are characterized by an increase of MS-related symptoms prior to natalizumab administration. The influence of extended interval dosing (EID) on wearing-off symptoms are important to consider, as this might cause hesitancy in initiating or continuing EID. METHODS: Participants of the NEXT-MS trial, in which treatment intervals are adjusted based on drug concentrations, were divided into two groups: an extended group containing participants with at least one week of additional interval extension, and a group with a fixed interval during the trial (range 4-7 weeks). Changes in the occurrence, frequency, onset, and severity of wearing-off symptoms were evaluated. RESULTS: 255 participants were included (extended group n = 171, fixed group n = 84). The odds on occurrence of wearing-off symptoms in the extended group did not increase after extending the treatment interval. Additional analyses for frequency, onset, and severity of wearing-off symptoms showed no changes over time. Mean decrease in natalizumab drug concentration did not influence the frequency of wearing-off symptoms. DISCUSSION: Wearing-off symptoms were not reinforced by further extending the natalizumab interval. Wearing-off symptoms might increase in a minority of patients after EID, although our data support the view that wearing-off symptoms appear to be unrelated to the decrease in natalizumab trough drug concentrations.

Removal of valproic acid by plasmapheresis in a patient treated for multiple sclerosis.

We present a case of a patient with multiple sclerosis who was treated with plasmapheresis and valproic acid. We used therapeutic drug monitoring to determine whether plasma concentrations of valproic acid were kept within the therapeutic window and to determine the amount of valproic acid that was removed by plasmapheresis.

Legionnaires disease in Europe, 2009-2010.

The surveillance of Legionnaires' disease (LD) in Europe is carried out by the European Legionnaires' Disease Surveillance Network (ELDSNet) and coordinated by the European Centre for Disease Prevention and Control (ECDC). All cases reported in 2009 and 2010 and meeting the European case definition were electronically transmitted to The European Surveillance System (TESSy) database. A total of 5,551 and 6,305 cases were reported by 29 European countries in 2009 and 2010, respectively. The age-standardised rate of all cases was 1.20 per 100,000 inhabitants in 2010, 12% higher than in 2009, which was consistent with the increasing trend observed since 2005. Most of this increase consisted of community-acquired cases reported by France, Germany and the Netherlands with dates of onset in August­September. The exceptionally hot summer of 2010 in some parts of Europe may have played a role in this increase.

Travel-associated Legionnaires' disease in Europe, 2010.

In 2010, the European surveillance network for travel-associated Legionnaires' disease (ELDSNet, previously EWGLINET) received reports of 864 cases of travel-associated Legionnaires' disease, of whom 24 were reported to have had a fatal outcome. As in previous years, a very low proportion of clinical isolates were obtained (45 cases, 5.6%). In the 2010 dataset, male cases outnumbered female cases by 2.6:1 and had a median age of 61 years (range: 21-96), while the median age for women was 63 years (range: 12-95). The network identified 100 new clusters in 2010, of which 44 involved only one case from each reporting country and would probably not have been detected by national surveillance schemes alone. The largest cluster (having 14 cases) was associated with a cruise ship. Legionella species were detected at 61 of the 100 accommodation site clusters investigated. The names of five accommodation sites were published on the ECDC website.

Child abuse: a common problem in Curaçao?

OBJECTIVE: To assess the prevalence of child abuse among high school students in Curacao. METHODS: A questionnaire survey among high school students up to 17 years of age was conducted. The questionnaire was based on existing literature and validated questionnaires. The questionnaire used was analysed and adapted to the situation in Curaçao by a panel of experts on child abuse. The primary objective was to gain insight into the incidence, prevalence and various forms of child abuse among students in Curaçao. Five forms of child abuse are distinguished in the literature: physical abuse, emotional abuse, sexual abuse, neglect and exploitation. Furthermore, the degree of confidence of the students in general practitioners (GPs) as care providers in the field of child abuse was explored. RESULTS: Questionnaires from 545 of the 628 respondents were included. In total, 43% of the respondents had ever-experienced an event which could be defined as (a form of) child abuse. More than one-third of the respondents reporting child abuse ever had an experience that could be interpreted as physical abuse. More than 15% of the respondents reporting child abuse had experienced sexual abuse. Girls experienced significantly more sexual abuse than boys. Emotional abuse in the last year was experienced by 3% of the respondents. One per cent of the respondents ever-experienced neglect. According to most respondents, GPs were not seen as care providers in cases of child abuse; they believed that GPs were mainly to be consulted for illnesses or physical symptoms and not for forms of child abuse. CONCLUSION: The prevalence of ever-having-experienced a form of child abuse is estimated at 431 per 1000 students. Child abuse, particularly physical abuse, is common in Curaçao, and is probably comparable to other surrounding countries. General practitioners were not seen as care providers in identifying and reporting cases of child abuse according to most respondents.

Mycobacterium tuberculosis retains viability in RNAlater buffer but not in GTC-TCEP and DNA/RNA Shield.

Efficient inactivation of clinical samples containing mycobacteria is crucial for biosafety during shipment and handling. When stored in RNAlater, Mycobacterium tuberculosis H37Ra remains viable, and our results suggest that at -20 °C and 4 °C changes in the mycobacterial transcriptome are possible. Only GTC-TCEP and DNA/RNA Shield inactivate sufficiently for shipment.

Bedaquiline- and clofazimine- selected Mycobacterium tuberculosis mutants: further insights on resistance driven largely by Rv0678.

Drug-resistant tuberculosis is a serious global health threat. Bedaquiline (BDQ) is a relatively new core drug, targeting the respiratory chain in Mycobacterium tuberculosis (Mtb). While mutations in the BDQ target gene, atpE, are rare in clinical isolates, mutations in the Rv0678 gene, a transcriptional repressor regulating the efflux pump MmpS5-MmpL5, are increasingly observed, and have been linked to worse treatment outcomes. Nevertheless, underlying mechanisms of (cross)-resistance remain incompletely resolved. Our study aims to distinguish resistance associated variants from other polymorphisms, by assessing the in vitro onset of mutations under drug pressure, combined with their impact on minimum inhibitory concentrations (MICs) and on protein stability. For this purpose, isolates were exposed in vitro to sub-lethal concentrations of BDQ or clofazimine (CFZ). Selected colonies had BDQ- and CFZ-MICs determined on 7H10 and 7H11 agar. Sanger sequencing and additional Deeplex Myc-TB and whole genome sequencing (WGS) for a subset of isolates were used to search for mutations in Rv0678, atpE and pepQ. In silico characterization of relevant mutations was performed using computational tools. We found that colonies that grew on BDQ medium had mutations in Rv0678, atpE or pepQ, while CFZ-exposed isolates presented mutations in Rv0678 and pepQ, but none in atpE. Twenty-eight Rv0678 mutations had previously been described among in vitro selected mutants or in patients' isolates, while 85 were new. Mutations were scattered across the Rv0678 gene without apparent hotspot. While most Rv0678 mutations led to an increased BDQ- and/or CFZ-MIC, only a part of them surpassed the critical concentration (69.1% for BDQ and 87.9% for CFZ). Among the mutations leading to elevated MICs for BDQ and CFZ, we report a synonymous Val1Val mutation in the Rv0678 start codon. Finally, in silico characterization of Rv0678 mutations suggests that especially the C46R mutant may render Rv0678 less stable.

Evaluating newly approved drugs in combination regimens for multidrug-resistant tuberculosis with fluoroquinolone resistance (endTB-Q): study protocol for a multi-country randomized controlled trial.

BACKGROUND: Treatment for fluoroquinolone-resistant multidrug-resistant/rifampicin-resistant tuberculosis (pre-XDR TB) often lasts longer than treatment for less resistant strains, yields worse efficacy results, and causes substantial toxicity. The newer anti-tuberculosis drugs, bedaquiline and delamanid, and repurposed drugs clofazimine and linezolid, show great promise for combination in shorter, less-toxic, and effective regimens. To date, there has been no randomized, internally and concurrently controlled trial of a shorter, all-oral regimen comprising these newer and repurposed drugs sufficiently powered to produce results for pre-XDR TB patients. METHODS: endTB-Q is a phase III, multi-country, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of a treatment strategy for patients with pre-XDR TB. Study participants are randomized 2:1 to experimental or control arms, respectively. The experimental arm contains bedaquiline, linezolid, clofazimine, and delamanid. The control comprises the contemporaneous WHO standard of care for pre-XDR TB. Experimental arm duration is determined by a composite of smear microscopy and chest radiographic imaging at baseline and re-evaluated at 6 months using sputum culture results: participants with less extensive disease receive 6 months and participants with more extensive disease receive 9 months of treatment. Randomization is stratified by country and by participant extent-of-TB-disease phenotype defined according to screening/baseline characteristics. Study participation lasts up to 104 weeks post randomization. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 324 participants across 2 arms affords at least 80% power to show the non-inferiority, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per-protocol populations. DISCUSSION: This internally controlled study of shortened treatment for pre-XDR TB will provide urgently needed data and evidence for clinical and policy decision-making around the treatment of pre-XDR TB with a four-drug, all-oral, shortened regimen. TRIAL REGISTRATION: ClinicalTrials.Gov NCT03896685. Registered on 1 April 2018; the record was last updated for study protocol version 4.3 on 17 March 2023.

Travel-associated Legionnaires disease in residents from England and Wales travelling to Corfu, Greece, August to October 2011.

Fourteen cases of Legionnaires' disease were confirmed in residents from England and Wales with history of travel to Corfu, Greece, in the 14 days before symptom onset. These cases were reported to the Health Protection Agency national surveillance scheme for Legionnaires' disease in residents of England and Wales between August and October 2011. In addition, one case in a Greek national and a case of non-pneumonic legionellosis in a resident from Scotland were also reported. Few cases shared the same accommodation site in Corfu during their incubation period. Epidemiological investigations and microbiological analysis of clinical and environmental samples excluded a single source but rather implicated several accommodation sites as sources of sporadic infection. Control measures have since been implemented at these accommodation sites and no further cases have been reported. This incident highlights the value of epidemiological typing and the importance of effective international response to control and prevent legionella infection.