Impact of COVID-19 restrictions on behavioural and psychological symptoms in home-dwelling people with dementia: A prospective cohort study (PAN.DEM)

Objectives To investigate the impact of the COVID-19 restrictions on behavioural and psychological symptoms of dementia (BPSD). Design Prospective cohort study (PAN.DEM) nested within the halted parent trial ([email protected]). Setting Households in Norway immediate before and 6–9 weeks into the COVID-19 restrictions. Participants 104 dyads (persons with mild to moderate dementia aged ≥65 and their informal carers) completed both prepandemic and pandemic assessments, among 237 in the parent trial. Mini-Mental Status Examination score 15–26 or Functional Assessment Staging score 3–7 covered dementia severity. Main outcome measures Neuropsychiatric Inventory (NPI-12) total (range 0–144), psychosis (range 0–24), hyperactive behaviour (range 0–60) and mood subsyndrome (range 0–48) scores; Cornell Scale for Depression in Dementia (CSDD) total score (range 0–38). Results We found an overall increase in BPSD by NPI-12 total score comparing prepandemic to pandemic levels (median 16 IQR (4.5–29) to 20 (7–32.5), p=0.03) over a mean of 86 days (SD 19). NPI-12 total score worsened in 57 (55%) of people with dementia and was associated with postponed or averted contacts with healthcare professionals (logistic regression, OR 3.96, 95% CI 1.05 to 14.95). Psychosis subsyndrome levels increased (0 (0–3) to 0.5 (0–6), p=0.01) in 37 (36%) persons; this worsening was associated with partial insight (9.57, 1.14 to 80.71) and reduced informal carer contact (4.45, 1.01 to 19.71). Moreover, depressive symptoms increased as assessed by CSDD total score (5 (3–9) to 7 (4–12), p=0.01) and worsened for 56 (54%), which was inversely associated with psychotropic drugs on-demand (0.16, 0.03 to 0.75). Conclusions BPSD worsened during the first months of the COVID-19 restrictions, most pronounced for psychosis and depression. These BPSD exacerbations have implications for pandemic policies, emphasising that restrictions must balance COVID-19 morbidity and mortality against dementia deterioration.publishedVersio

Proteases of haematophagous arthropod vectors are involved in blood-feeding, yolk formation and immunity : a review

Ticks, triatomines, mosquitoes and sand flies comprise a large number of haematophagous arthropods considered vectors of human infectious diseases. While consuming blood to obtain the nutrients necessary to carry on life functions, these insects can transmit pathogenic microorganisms to the vertebrate host. Among the molecules related to the blood-feeding habit, proteases play an essential role. In this review, we provide a panorama of proteases from arthropod vectors involved in haematophagy, in digestion, in egg development and in immunity. As these molecules act in central biological processes, proteases from haematophagous vectors of infectious diseases may influence vector competence to transmit pathogens to their prey, and thus could be valuable targets for vectorial control

Functional tests of structural models for abortive cycling in T7 RNA polymerase

Transcription initiates when the enzyme binds to the promoter region and melts open an initial transcribing bubble that extends from position -4 to +4. The initiation phase continues until the enzyme synthesizes ∼8mer RNA, at which point T7 RNA polymerase begins its transition into the elongation phase. The initiation phase is characterized by a energetic instability, which leads to release of small RNA 2-8 bases in length, known as abortive cycling. Abortive cycling, which is the release of small RNA transcripts during synthesis of the first 8 bases of a transcript, has been well documented in most single and multisubunit RNA polymerases, and has been shown to occur in vivo. Structural studies have prompted the ‘scrunched intermediate’ mechanistic model (an elaboration of the earlier stressed intermediate model), which proposes that compaction of the upstream template DNA within the enzyme and/or expansion of the bubble during initiation leads to instability and the release of abortive RNAs. T7 polymerases represent one of the most well characterized transcription systems and despite having no structural similarities to other multi subunit polymerases, shares very similar fundamental mechanistic features. In the initially transcribing abortive phase, the bubble expands as the initial RNA:DNA hybrid grows and the hybrid pushes on components of the enzyme: both key features in the proposed scrunching mechanism. In this work, we directly test predictions of the scrunching model. The introduction of nicks or gaps into the template (scrunched) strand should reduce stress and therefore reduce abortive. Similarly, the introduction of extra bases in this region should increase the release of abortive RNAs or shift their profile to shorter lengths. For all of these modifications, our results show no systematic change in the abortive amounts or profile. An alternate model predicts that a critical source of stress during abortive initiation is the stress caused by the steric clash of the DNA-RNA hybrid against the N-terminal domain. It is already known that this steric clash leads to the transition of the enzyme into a stable elongation complex, however it is unclear as to whether it induces energetic instability within the system. By introducing bulk at the 5’ end of an initiating RNA primer we have increased the putative stress of the DNA-RNA primer against the N terminal domain and demonstrated a slight increase in the release of abortive products. The increase in abortive RNA was however not systematic and even with an increase in the steric push, the enzyme continues to transition into the elongation phase and make run off RNA. Our results suggest that abortive cycling is a kinetically controlled process as opposed to any structurally mediated mechanism

Functional Tests Of Structural Models For Abortive Cycling In T7 RNA Polymerase

Transcription initiates when the enzyme binds to the promoter region and melts open an initial transcribing bubble that extends from position -4 to +4. The initiation phase continues until the enzyme synthesizes ∼8mer RNA, at which point T7 RNA polymerase begins its transition into the elongation phase. The initiation phase is characterized by a energetic instability, which leads to release of small RNA 2-8 bases in length, known as abortive cycling. Abortive cycling, which is the release of small RNA transcripts during synthesis of the first 8 bases of a transcript, has been well documented in most single and multisubunit RNA polymerases, and has been shown to occur in vivo. Structural studies have prompted the \u27scrunched intermediate\u27 mechanistic model (an elaboration of the earlier stressed intermediate model), which proposes that compaction of the upstream template DNA within the enzyme and/or expansion of the bubble during initiation leads to instability and the release of abortive RNAs. T7 polymerases represent one of the most well characterized transcription systems and despite having no structural similarities to other multi subunit polymerases, shares very similar fundamental mechanistic features. In the initially transcribing abortive phase, the bubble expands as the initial RNA:DNA hybrid grows and the hybrid pushes on components of the enzyme: both key features in the proposed scrunching mechanism. In this work, we directly test predictions of the scrunching model. The introduction of nicks or gaps into the template (scrunched) strand should reduce stress and therefore reduce abortive. Similarly, the introduction of extra bases in this region should increase the release of abortive RNAs or shift their profile to shorter lengths. For all of these modifications, our results show no systematic change in the abortive amounts or profile. An alternate model predicts that a critical source of stress during abortive initiation is the stress caused by the steric clash of the DNA-RNA hybrid against the N-terminal domain. It is already known that this steric clash leads to the transition of the enzyme into a stable elongation complex, however it is unclear as to whether it induces energetic instability within the system. By introducing bulk at the 5\u27 end of an initiating RNA primer we have increased the putative stress of the DNA-RNA primer against the N terminal domain and demonstrated a slight increase in the release of abortive products. The increase in abortive RNA was however not systematic and even with an increase in the steric push, the enzyme continues to transition into the elongation phase and make run off RNA. Our results suggest that abortive cycling is a kinetically controlled process as opposed to any structurally mediated mechanism