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- Björnfot, Cecilia, et al.
(författare)
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Cerebral arterial stiffness is linked to white matter hyperintensities and perivascular spaces in older adults : a 4D flow MRI study
- 2024
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : Sage Publications. - 0271-678X .- 1559-7016.
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Tidskriftsartikel (refereegranskat)abstract
- White matter hyperintensities (WMH), perivascular spaces (PVS) and lacunes are common MRI features of small vessel disease (SVD). However, no shared underlying pathological mechanism has been identified. We investigated whether SVD burden, in terms of WMH, PVS and lacune status, was related to changes in the cerebral arterial wall by applying global cerebral pulse wave velocity (gcPWV) measurements, a newly described marker of cerebral vascular stiffness. In a population-based cohort of 190 individuals, 66–85 years old, SVD features were estimated from T1-weighted and FLAIR images while gcPWV was estimated from 4D flow MRI data. Additionally, the gcPWV’s stability to variations in field-of-view was analyzed. The gcPWV was 10.82 (3.94) m/s and displayed a significant correlation to WMH and white matter PVS volume (r = 0.29, p < 0.001; r = 0.21, p = 0.004 respectively from nonparametric tests) that persisted after adjusting for age, blood pressure variables, body mass index, ApoB/A1 ratio, smoking as well as cerebral pulsatility index, a previously suggested early marker of SVD. The gcPWV displayed satisfactory stability to field-of-view variations. Our results suggest that SVD is accompanied by changes in the cerebral arterial wall that can be captured by considering the velocity of the pulse wave transmission through the cerebral arterial network.
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- Kalniņš, Aigars, 1990-
(författare)
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Studies in Latvian Comparative Dialectology : —with special focus on word-final *–āj(s)/*–ēj(s) and *–āji(s)/*–ēji(s)
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The thesis consists of four interconnected studies of various topics in the fields of Latvian dialectology and historical linguistics: (1) apocope and shortening; (2) loss of the present 2nd singular endings *–i and *–ɨ; (3) the development of the participle desinences *–ājis *–ējis; (4) the ā– and ē–stem locative singular endings. A recurrent theme is a potential loss of *j in the phonological sequences *–āji(s) *–ēji(s), which were subsequently contracted to *–āj(s) *–ēj(s). In this regard, the first study provides the necessary East Baltic context, while studies 2, 3 and 4 investigate the relevant evidence in the Latvian dialects. At the same time, however, each of the topics is also studied on its own terms.In the first study, an improved account of apocope and shortening is formulated. It is argued that the primary apocope affected all unaccented short vowels, including *u, but that it took place before the accent retraction. Endings that were only affected in immobile paradigms were restored on the model of their counterparts in mobile paradigms. The secondary apocope in second posttonic syllables, which traditionally accounts for the occasional loss of inherited long vowels and diphthongs, is dated after accent retraction but restricted to *i. This implies that a series of endings such as d.sg. –am, d.pl. –Vms, ill.sg. –Vn, 1.pl. –Vm a.o. contained short vowels when the primary apocope set in. Unless Leskien’s Law operated in Latvian, the evidence suggests that the final vowels in these endings were short. If Lithuanian excludes Leskien’s Law in a given case, then the Latvian evidence is compelling, e.g., PEB d.sg.m. *–amu or *–ami rather than *–amọ̄(i̯).The second study investigates present 2nd singular forms with and without a distinct ending in the Latvian dialects. The most archaic distribution seems to be the one found in Blīdene106, where only the derived presents are endingless in the indicative. Studies 2, 3 and 4 also give a comprehensive overview of the development of word-final *–āj(s) *–ēj(s) and *–āji(s) *–ēji(s). Both *–āj *–ēj and *–āji *–ēji yielded –ā –ē in Low Latvian, while High Latvian might have a contrast between accented –āi̯ –ēi̯ and unaccented –ā –ē. High Latvian reflects *–ājs *–ējs and *–ājis *–ējis as –ājs –ējs, but the Low Latvian developments are unclear. Accented *–ājs *–ējs yield –āš –ēš but in unaccented position there may be up to three phonologically regular reflexes: –āš –ēš, –aiš –eiš and –ais –eis. In Vidzeme and Zemgale, *–ājis *–ējis must have merged with *–ājs *–ējs, but in Courland *–ājis *–ējis were possibly apocopated only after *–ājs *–ējs had become –āš –ēš.Accordingly, only Low Latvian –â –ê can be reflexes of the old inessive. Low Latvian –ai –ei cannot be cognate with –â –ê but might continue the old adessive. If Low Latvian –ã2 –ẽ2 reflect the illative, then the three pairs, along with dialectal adverbs in –uop, represent all four East Baltic local cases, which therefore must have existed at least as syntactic constructions in Proto–East Baltic. The enigmatic High Latvian ā–stem locative singular ending –â is identified with Low Latvian –ai rather than –â, which explains its remarkable lack of labialisation but implies a development *–ˌaî > –ˌâ.The utility of the proposed phonetic loss of *j is limited to disyllabic forms like l.sg. *tâji ‘that’ prs.2.sg. *smeji ‘laugh’ ptc. *gãjis ‘go,’ all of which might also be analogical, and it seems best to reject it.
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- Larsson, Jenny, 1990-
(författare)
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Population-based studies of higher-level gait disorders and hydrocephalus : focused on brain ventricular morphometry and patient outcomes following shunt surgery
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: To study gait is of great importance for the health of the aging population. Higher-level gait disorders (HLGD) are characterized by a slow, symmetrical, unsteady gait. Its cause is most often unknown. HLGD in combination with ventriculomegaly (i.e., large brain ventricles) is obligatory for the diagnosis of Idiopathic Normal pressure hydrocephalus (INPH), a syndrome that is sometimes treatable with insertion of a CSF shunt. It is therefore important to investigate the prevalence of HLGD in the population and brain morphometry in individuals with HLGD. Further, self-perceived confidence in gait and balance among patients with HLGD and INPH is unknown and important to study as slow gait velocity is associated with falls, injuries, and death. CSF shunts in INPH are associated with adverse events and little is known about epilepsy after surgery or minor and moderate adverse events such as headache and abdominal pain.Objective: In the older population investigate the prevalence of HLGD, and its association to ventriculomegaly. To investigate quality of life (QoL), depressive symptoms, and balance confidence in an HLGD population. In patients shunted for INPH, assess falls, fear of falling, balance confidence and prevalence of the possible adverse events headache, epilepsy, and abdominal pain after shunt surgery. Methods: Two population-based case-controlled cohorts were studied. In the first study, the "Ventriculomegaly and gait disturbance in the senior population in the region of Västerbotten" (VESPR) study, individuals (65-84 years) were recruited through a questionnaire (n=6467 dispatched). The final population consisted of 798 cases with gait disorders and 249 controls without gait disorders, age- and sex-matched to individuals with HLGD. All had been examined by a physician and were categorized: 1. "HLGD"; 2. "neurological gait disorder"; 3. "non-neurological gait disorder" or; 4. "no gait disorder". Participants were assessed with: the Swedish modification of the Falls-Efficacy Scale (FES(S)), the Modified Gait-Efficacy Scale (mGES), the Euro Quality of Life 5-Dimension 5-Level (EQ5D5L) instrument (EQ5D5L index and Euro Quality of life visual analogue scale (EQ VAS)) and the Geriatric depression scale 15 (GDS-15). Cases and controls had an MRI of the brain and ventricular size was measured. The second study, the "Comorbidities and vascular risk factors associated with idiopathic normal pressure hydrocephalus" (INPH-CRasH) study, consisted of 176 shunted INPH patients and 368 age- and sex-matched controls. Mean age was 74 years in INPH and 73 in controls. All had a visit to a healthcare facility. Information regarding adverse events, falls and fear of falling were gathered through a questionnaire. Additional information on diagnoses and prescribed drugs were obtained from the Swedish national patient- and drug registries. Data was compared between the groups, and before- and after surgery for INPH. Results: In the VESPR study, 87 individuals were categorized as HLGD, corresponding to a prevalence of 5.8% (95% confidence interval (CI) 4.6-7.0) in the older population. A definite cause was found in 13% (n=11) of individuals with HLGD, but ventriculomegaly was present in 63% (n=46/73, controls: 38%, n=70/184; OR 2.8 95% CI 1.6-4.9, p<0.001). HLGD had more depressive symptoms and lower quality of life (QoL), compared with individuals without gait disorder (GDS-15: 3.9±3.4 vs. 2.5±2.8, p=0.004; EQ VAS: 63±17 vs. 71±18; p<0.001; EQ5D5L index: 0.671±0.188 vs. 0.840±0.126, p<0.001). HLGD had low confidence in gait and to avoid falls compared to those without gait disorder (mGES: 60±22 vs. 74±21; p<0.001; FES(S): 93±32 vs. 111±25 p<0.001). The INPH-CRasH study revealed that patients with INPH feared falling more often (3.3±1.1) and had lower balance confidence (78±40) than controls (fear of falling: 1.6±0.9, balance confidence: 126±14; p<0.001 in both comparisons). After surgery, the proportions were reduced in INPH (p<0.001). More INPH than controls were fallers (before surgery: 67% vs. 11% OR 15.48 95% CI 9.85-24.32; after surgery: 35% vs 11% OR 4.15 95% CI 2.65-6.50, p<0.001). The proportion was reduced after surgery (p<0.001). In shunted INPH, epilepsy, antiepileptic drug (AED) treatment and headache was more common than in controls (epilepsy: 4.5% vs. 1.1% OR 4.3, 95% CI 1.3-14.6, p=0.023; AED treatment: 14.8% vs. 7.3% OR 0.5 95% CI 0.3-0.8, p=0.010; headache: 36.1% vs 11.6% OR 0.2 95% CI 0.2-0.4, p<0.001). Forty percent INPH (n=70) had abdominal pain after surgery. Conclusions: HLGD was common in the general older population and associated to ventriculomegaly. HLGD was also associated with low quality of life and depressive symptoms. Both individuals with HLGD and patients with INPH had low confidence in their balance but it was less common after surgery for INPH. However, patients shunted for INPH still had more problems with low balance confidence, falls, and fear of falling than controls. After shunt surgery for INPH, a significant portion of patients developed epilepsy, headache, and abdominal pain. The findings motivate investigations of causal relationships between HLGD and ventriculomegaly and if treatment options exist for HLGD. The observed adverse events in patients shunted for INPH should be considered in pre- and postoperative evaluations of shunt surgery, and in the development of new techniques for shunt placement. Additional interventions directed towards low balance confidence, falls and fear of falling should be considered for patients with INPH, and for individuals with HLGD.
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- Mezheyeuski, Artur, et al.
(författare)
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An immune score reflecting pro- and anti-tumoural balance of tumour microenvironment has major prognostic impact and predicts immunotherapy response in solid cancers
- 2023
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Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 88
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cancer immunity is based on the interaction of a multitude of cells in the spatial context of the tumour tissue. Clinically relevant immune signatures are therefore anticipated to fundamentally improve the accuracy in predicting disease progression.Methods: Through a multiplex in situ analysis we evaluated 15 immune cell classes in 1481 tumour samples. Single-cell and bulk RNAseq data sets were used for functional analysis and validation of prognostic and predictive associations.Findings: By combining the prognostic information of anti-tumoural CD8+ lymphocytes and tumour supportive CD68+CD163+ macrophages in colorectal cancer we generated a signature of immune activation (SIA). The prognostic impact of SIA was independent of conventional parameters and comparable with the state-of-art immune score. The SIA was also associated with patient survival in oesophageal adenocarcinoma, bladder cancer, lung adenocarcinoma and melanoma, but not in endometrial, ovarian and squamous cell lung carcinoma. We identified CD68+CD163+ macrophages as the major producers of complement C1q, which could serve as a surrogate marker of this macrophage subset. Consequently, the RNA-based version of SIA (ratio of CD8A to C1QA) was predictive for survival in independent RNAseq data sets from these six cancer types. Finally, the CD8A/C1QA mRNA ratio was also predictive for the response to checkpoint inhibitor therapy.Interpretation: Our findings extend current concepts to procure prognostic information from the tumour immune microenvironment and provide an immune activation signature with high clinical potential in common human cancer types.
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