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Abstract This case report presents a 38‐year‐old male patient who, after a febrile infection, developed super‐refractory status epilepticus and multiorgan failure, and died in 2 weeks despite the best possible intensive care. Autopsy revealed findings suggestive of hemophagocytic lymphohistiocytosis (HLH). This case shows that a rare immunological cause such as HLH may cause febrile infection‐related epilepsy syndrome (FIRES), and complications of intensive care can mask the physiological and laboratory changes in HLH. Plain Language Summary This case report presents a 38‐year‐old man who, after a febrile infection, developed intractable epileptic activity requiring intensive care treatment. During the intensive care, the patient showed signs of multiple organ damage and died in 2 weeks despite the best possible treatment. Autopsy revealed findings suggestive of hemophagocytic lymphohistiocytosis (HLH), which is a rare immune system regulation disorder leading to persistent inflammatory state and organ damages. This case shows that an immunological disorder like HLH may underlie treatment resistant fever‐related epileptic seizures.

BackgroundHelsinki University Hospital has developed a digital care pathway (DCP) for people with multiple sclerosis (MS) to improve the care quality. DCP was designed for especially newly diagnosed patients to support adaptation to a chronic disease. ObjectiveThis study investigated the MS DCP user behavior and its impact on patient education-mediated changes in health care use, patient-perceived impact of MS on psychological and physical functional health, and patient satisfaction. MethodsWe collected data from the service launch in March 2020 until the end of 2022 (observation period). The number of users, user logins, and their timing and messages sent were collected. The association of the DCP on health care use was studied in a case-control setting in which patients were allowed to freely select whether they wanted to use the service (DCP group n=63) or not (control group n=112). The number of physical and remote appointments either to a doctor, nurse, or other services were considered in addition to emergency department visits and inpatient days. The follow-up time was 1 year (study period). Furthermore, a subgroup of 36 patients was recruited to fill out surveys on net promoter score (NPS) at 3, 6, and 12 months, and their physical and psychological functional health (Multiple Sclerosis Impact Scale) at 0, 3, 6, and 12 months. ResultsDuring the observation period, a total of 225 patients had the option to use the service, out of whom 79.1% (178/225) logged into the service. On average, a user of the DCP sent 6.8 messages and logged on 7.4 times, with 72.29% (1182/1635) of logins taking place within 1 year of initiating the service. In case-control cohorts, no statistically significant differences between the groups were found for physical doctors’ appointments, remote doctors’ contacts, physical nurse appointments, remote nurse contacts, emergency department visits, or inpatient days. However, the MS DCP was associated with a 2.05 (SD 0.48) visit increase in other services, within 1 year from diagnosis. In the prospective DCP-cohort, no clinically significant change was observed in the physical functional health between the 0 and 12-month marks, but psychological functional health was improved between 3 and 6 months. Patient satisfaction improved from the NPS index of 21 (favorable) at the 3-month mark to the NPS index of 63 (excellent) at the 12-month mark. ConclusionsThe MS DCP has been used by a majority of the people with MS as a complementary service to regular operations, and we find high satisfaction with the service. Psychological health was enhanced during the use of MS DCP. Our results indicate that DCPs hold great promise for managing chronic conditions such as MS. Future studies should explore the potential of DCPs in different health care settings and patient subgroups.

Introduction: Executive functions and processing speed have been regarded as core cognitive domains affected in cerebral small vessel disease (SVD). Executive functions, as an umbrella concept, consist of a variety of different subcomponents, yet in research these abilities are often evaluated with single tests or summary scores. Currently, it is unknown whether all executive abilities are equally affected by SVD brain changes and whether some tests are more sensitive in detecting deficits than others. We investigated the associations of white matter hyperintensity (WMH) volume with specific executive abilities (cognitive flexibility, response inhibition, working memory) and processing speed by using an extensive set of paper-and-pencil and computerised neuropsychological tests. Methods: In the Helsinki Small Vessel Disease Study, 152 subjects (age 65-75 years) with varying degrees of WMH but no clinical stroke or dementia were evaluated with quantitative automated MRI analysis and a comprehensive neuropsychological examination. Executive functions and processing speed measures included the Wechsler adult intelligence scale (WAIS-IV) Coding subtest, Stroop test, Hayling sentence completion test, Brixton spatial anticipation test, verbal fluency test, Wechsler memory scale (WMS-III) Digit span and Number-letter sequencing subtasks, and the more experimental Flexible attention test (FAT), Simon task and Sustained attention to response task (SART). Results: Linear regression analyses controlling for age, sex and education revealed significant associations between WMH volume and measures within all evaluated subdomains. However, marked differences were found between individual test Results: The strongest associations were observed for FAT Numbers and Number-letter task (computerised tests based on the Trail making test), FAT Visuospatial span, Simon task and verbal fluency (animals), while some of the widely used tests failed to reach significance. Discussion: WMH are related to significant deficits in processing speed and executive functions subdomains of flexibility, inhibition and working memory. The strength of associations within subdomains is nevertheless highly dependent on the evaluation method in use. Computerised tests providing precise measures of reaction times and response accuracy seem to outperform many of the conventional paper-and-pencil tests. These results have implications for observational studies and intervention trials, where the selection of sensitive outcome measures is crucial.

Introduction: Subjective cognitive complaints are common in patients with cerebral small vessel disease (SVD), yet their correspondence to informant evaluations, objective cognitive functions and severity of brain changes are poorly understood. We studied the associations of subjective and informant reports of cognitive difficulties (executive functions and memory) with findings from a comprehensive neuropsychological assessment and brain MRI (white matter hyperintensities, WMH volume) as well as depressive symptoms and functional abilities (instrumental activities of daily living, IADL). Methods: In the Helsinki SVD Study, 152 older adults with varying degrees of WMH but without stroke or dementia were classified as having normal cognition or mild cognitive impairment (MCI) based on Jak/Bondi neuropsychological criteria. The objective cognitive measures also included continuous domain scores for memory and executive functions. Cognitive complaints were evaluated with the subjective- and informant-versions of Prospective and Retrospective Memory Questionnaire (PRMQ) and Dysexecutive Questionnaire (DEX), functional abilities with the Amsterdam IADL Questionnaire and depressive symptoms with the Geriatric Depression Scale (GDS-15). Results: Subjective cognitive complaints correlated significantly with informant reports (r=0.40-0.50, p0.05). Instead, subjective DEX (OR 1.10, CI 95% 1.05-1.16, p

Abstract Background The aim of this study was to identify early clinical features of patients with new-onset refractory status epilepticus (NORSE) that could direct the treatment in the first days of hospitalisation. Methods A retrospective cohort study of adult NORSE patients treated in the intensive care units of Helsinki University Hospital 2007-2018. Results We found 19 adult NORSE patients who divided into three subgroups on the basis of their clinical features: viral encephalitis (n = 5, 26%), febrile infection-related epilepsy syndrome (FIRES) (n = 6, 32%) and afebrile NORSE (n = 8, 42%). FIRES and afebrile NORSE patients remained without confirmed etiology, but retrospectively two paraneoplastic and two neurodegenerative causes were suspected in the afebrile NORSE group. Viral encephalitis patients were median 64 years old (IQR 55-64), and four (80%) had prodromal fever and abnormal findings in the first brain imaging. FIRES patients were median 21 years old (IQR 19-24), all febrile and had normal brain imaging at onset. In the afebrile NORSE group, median age was 67 (IQR 59-71) and 50% had prodromal cognitive or psychiatric symptoms. FIRES patients differed from other NORSE patients by younger age (p = 0.001), respiratory prodromal symptoms (p = 0.004), normal brain MRI (p = 0.044) and lack of comorbidities (p = 0.011). They needed more antiseizure medications (p = 0.001) and anesthetics (p = 0.002), had a longer hospital stay (p = 0.017) and more complications (p

IgG4-related disease (IgG4-RD) is an emerging immune-mediated chronic fibrotic disease characterized by tumour-like mass formation. Reports of brain parenchymal involvement in IgG4-RD are rare and complete treatment-related remission of lesions has never been reported. Here, we present a woman in her mid-50s who developed headache and seizures. Brain magnetic resonance imaging revealed frontal bilateral pachymeningitis and a left frontal lobe parenchymal lesion, and pathologic findings were consistent with an IgG4-RD central nervous system manifestation. She had a history of tumour-like growth around the right optic nerve, orbital and maxillary cavities treated successfully with corticosteroids 28 years ago, and was receiving infliximab as a maintenance therapy for uveitis for the last 14 years. After initial high-dose corticosteroid treatment, the patient was treated with rituximab, and after 3 months, the patient presented with complete remission of IgG4-RD lesions and associated symptoms. This case illustrates the chronic, decades-spanning nature of IgG4-RD, and a complete response to rituximab even with intracerebral mass lesions that had emerged despite the use of infliximab, a therapy previously reported successful in IgG4-RD.

As evidence of adverse health effects due to air pollution continues to increase, the World Health Organization (WHO) recently published its latest edition of the global air quality guidelines (World Health Organization, 2021). Although not legally binding, the guidelines aim to provide a framework in which policymakers can combat air pollution by formulating evidence-based air quality management strategies. In the light of this, the European Union has stated its intent to revise the current ambient air quality directive (2008/50/EC) to more closely resemble the newly published WHO guidelines (European Commission, 2020). This article provides an informed opinion on selected features of the air quality directive that we believe would benefit from a reassessment. The selected features include discussion about (1) air quality sensors as a part of a hierarchical observation network, (2) the number of minimum sampling points and their siting criteria, and (3) new target air pollution parameters for future consideration.

Objective: Subjective cognitive complaints are common in patients with cerebral small vessel disease (cSVD), yet their relationship with informant evaluations, objective cognitive functions and severity of brain changes are poorly understood. We studied the associations of subjective and informant reports with findings from comprehensive neuropsychological assessment and brain MRI. Method: In the Helsinki SVD Study, 152 older adults with varying degrees of white matter hyperintensities (WMH) but without stroke or dementia were classified as having normal cognition or mild cognitive impairment (MCI) based on neuropsychological criteria. The measures also included continuous domain scores for memory and executive functions. Cognitive complaints were evaluated with the subjective and informant versions of the Prospective and Retrospective Memory Questionnaire (PRMQ) and Dysexecutive Questionnaire (DEX); functional abilities with the Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL); and depressive symptoms with the Geriatric Depression Scale (GDS-15). Results: Subjective cognitive complaints correlated significantly with informant reports (r=0.40–0.50, p

ABSTRACT The Genomics Education Partnership (GEP) engages students in a course-based undergraduate research experience (CURE). To better understand the student attributes that support success in this CURE, we asked students about their attitudes using previously published scales that measure epistemic beliefs about work and science, interest in science, and grit. We found, in general, that the attitudes students bring with them into the classroom contribute to two outcome measures, namely, learning as assessed by a pre- and postquiz and perceived self-reported benefits. While the GEP CURE produces positive outcomes overall, the students with more positive attitudes toward science, particularly with respect to epistemic beliefs, showed greater gains. The findings indicate the importance of a student’s epistemic beliefs to achieving positive learning outcomes.

A hallmark of the research experience is encountering difficulty and working through those challenges to achieve success. This ability is essential to being a successful scientist, but replicating such challenges in a teaching setting can be difficult. The Genomics Education Partnership (GEP) is a consortium of faculty who engage their students in a genomics Course-Based Undergraduate Research Experience (CURE). Students participate in genome annotation, generating gene models using multiple lines of experimental evidence. Our observations suggested that the students’ learning experience is continuous and recursive, frequently beginning with frustration but eventually leading to success as they come up with defendable gene models. In order to explore our “formative frustration” hypothesis, we gathered data from faculty via a survey, and from students via both a general survey and a set of student focus groups. Upon analyzing these data, we found that all three datasets mentioned frustration and struggle, as well as learning and better understanding of the scientific process. Bioinformatics projects are particularly well suited to the process of iteration and refinement because iterations can be performed quickly and are inexpensive in both time and money. Based on these findings, we suggest that a dynamic of “formative frustration” is an important aspect for a successful CURE.

The Task Force on Diabetes and Cardiovascular diseases of the European Society of Cardiology and of the European Association for the Study of Diabetes.European Heart Journal (2007) 28, 88-136.

The Task Force on Diabetes and Cardiovascular diseases of the European Society of Cardiology and of the European Association for the Study of Diabetes.

The Task Force on Diabetes and Cardiovascular diseases of the European Society of Cardiology and of the European Association for the Study of Diabetes.

The Task Force on Diabetes and Cardiovascular diseases of the European Society of Cardiology and of the European Association for the Study of Diabetes.European Heart Journal (2007) 28, 88-136.

The phenotypic heterogeneity that characterizes human cancers reflects the enormous genetic complexity of the oncogenic process. This complexity can also be seen in mouse models where it is frequently observed that in addition to the initiating genetic alteration, the resulting tumor harbors additional, somatically acquired mutations that affect the tumor phenotype. To investigate the role of genetic interactions in the development of tumors, we have made use of the Emu-myc model of pre-B and B cell lymphoma. Since various studies point to a functional interaction between Myc and the Rb/E2F pathway, we have investigated the role of E2F activities in the process of Myc-induced lymphomagenesis. Whereas the absence of E2F1 and E2F3 function has no impact on Myc-mediated tumor development, the absence of E2F2 substantially accelerates the time of tumor onset. Conversely, tumor development is delayed by the absence of E2F4. The enhanced early onset of tumors seen in the absence of E2F2 coincides with an expansion of immature B lineage cells that are likely to be the target for Myc oncogenesis. In contrast, the absence of E2F4 mutes the response of the lineage to Myc and there is no expansion of immature B lineage cells. We also find that distinct types of tumors emerge from the Emu-myc mice, distinguished by different patterns of gene expression, and that the relative proportions of these tumor types are affected by the absence of either E2F2 or E2F4. From these results, we conclude that there are several populations of tumors that arise from the Emu-myc model, reflecting distinct populations of cells that are susceptible to Myc-mediated oncogenesis and that the proportion of these cell populations is affected by the presence or absence of E2F activities.

The V1/V2 region and the V3 loop of the human immunodeficiency virus type I (HIV-1) envelope (Env) protein are targets for neutralizing antibodies and also play an important functional role, with the V3 loop largely determining whether a virus uses CCR5 (R5), CXCR4 (X4), or either coreceptor (R5X4) to infect cells. While the sequence of V3 is variable, its length is highly conserved. Structural studies indicate that V3 length may be important for interactions with the extracellular loops of the coreceptor. Consistent with this view, genetic truncation of the V3 loop is typically associated with loss of Env function. We removed approximately one-half of the V3 loop from three different HIV-1 strains, and found that only the Env protein from the R5X4 strain R3A retained some fusion activity. Loss of V1/V2 (DeltaV1/V2) was well tolerated by this virus. Passaging of virus with the truncated V3 loop resulted in the derivation of a virus strain that replicated with wild-type kinetics. This virus, termed TA1, retained the V3 loop truncation and acquired several adaptive changes in gp120 and gp41. TA1 could use CCR5 but not CXCR4 to infect cells, and was extremely sensitive to neutralization by HIV-1 positive human sera, and by antibodies to the CD4 binding site and to CD4-induced epitopes in the bridging sheet region of gp120. In addition, TA1 was completely resistant to CCR5 inhibitors, and was more dependent upon the N-terminal domain of CCR5, a region of the receptor that is thought to contact the bridging sheet of gp120 and the base of the V3 loop, and whose conformation may not be greatly affected by CCR5 inhibitors. These studies suggest that the V3 loop protects HIV from neutralization by antibodies prevalent in infected humans, that CCR5 inhibitors likely act by disrupting interactions between the V3 loop and the coreceptor, and that altered use of CCR5 by HIV-1 associated with increased sensitivity to changes in the N-terminal domain can be linked to high levels of resistance to these antiviral compounds.