Dual target deep brain stimulation for complex essential and dystonic tremor - A 5-year follow up.

BACKGROUND: Essential tremor (ET) is characterized by action tremor of the upper limbs, head tremor and voice tremor. Dystonic tremor (DT) is produced by muscle contractions in a body affected by dystonia. Deep brain stimulation (DBS) of ventral intermediate nucleus of the thalamus (VIM) is the most well-known advanced treatment for medication-refractory tremor. However, decline in efficacy overtime has led to explore other targets. This study aimed to measure the efficacy of bilateral dual targeting ViM/caudal Zona Incerta (cZI) stimulation on tremor control. A secondary aim was to evaluate if there was a difference in the efficacy between ET and DT. METHODS: 36 patients were retrospectively recruited at the Walton NHS Foundation Trust, Liverpool, UK. Patients were assessed pre-operatively, and then at 1-year, 3-years, and 5-years post-operatively with the following scales: Fahn-Tolosa-Marin tremor rating (FTMTR) scale, EuroQol-5D, and Hospital Anxiety and Depression Scale. RESULTS: Bilateral ViM-cZI DBS significantly improved overall tremor score by 45.1% from baseline to 3-years post-operatively (p < 0.001). It continued to show improvement in overall FTMTR score by 30.7% at 5-years but this failed to meet significance. However, there was no significant improvement of mood or quality of life (QoL) scores. ET group on average showed a significant better clinical outcome compared to the DT group (p > 0.001). CONCLUSIONS: Our study found that bilateral ViM-cZI DBS treatment had a favourable effect on motor symptoms sustained over the 5-years in tremor patients, especially in ET group. There was limited effect on mood and QoL with similar trends in outcomes for both tremor types.

Methods to refine and extend a Pregnancy Register in the UK Clinical Practice Research Datalink primary care databases.

PURPOSE: Real-world data represents a valuable tool for pregnancy research. However, an algorithmic approach is needed to ascertain pregnancy timings from this complex data. The Clinical Practice Research Datalink (CPRD) GOLD Pregnancy Register, based on UK Primary care data, has therefore proven to be a valuable research tool. The same algorithmic approach was applied to the CPRD Aurum data to generate an equivalent register in the larger database. METHODS: Records of female patients registered with a CPRD Aurum contributing practice between the 1st of January 1987 and the 30th of April 2021 were searched for evidence of pregnancy. The algorithm used to generate the CPRD GOLD Pregnancy Register was redeveloped and applied first to CPRD GOLD and then to CPRD Aurum. The resulting CPRD Aurum Pregnancy Register was validated against the CPRD GOLD register, linked Hospital Episode Statistics (HES) and the Office of National Statistics (ONS) live birth data. RESULTS: There are 16 833 427 pregnancy episodes in the CPRD Aurum Pregnancy Register from 6 724 615 women, more than double the number in CPRD GOLD. The distribution of pregnancy outcome types was comparable between the registers. Across the whole register, there was good concordance between pregnancy episodes found in CPRD Aurum and linked HES. However, both CPRD registers saw a declining number of pregnancy episodes from 2007 onwards, steeper than in HES or the ONS birth data. CONCLUSIONS: A pregnancy register has been created in CPRD Aurum. Changes in antenatal care policies in the UK have led to declining numbers of pregnancies in EHR primary care data. However, the creation of this pregnancy register has tripled the number of patients in the CPRD Pregnancy Registers and will increase the capacity to study pregnancy in CPRD data, particularly rare or emerging exposures, and outcomes.

The feasibility of pragmatic influenza vaccine randomized controlled real-world trials in Denmark and England.

We estimated the frequency of non-specific influenza-associated clinical endpoints to inform the feasibility of pragmatic randomized controlled trials (RCT) assessing relative vaccine effectiveness (rVE). Hospitalization rates of respiratory, cardiovascular and diabetic events were estimated from Denmark and England's electronic databases and stratified by age, comorbidity and influenza vaccination status. We included a seasonal average of 4.5 million Danish and 7.2 million English individuals, 17 and 32% with comorbidities. Annually, approximately 1% of Danish and 0.5% of English individuals were hospitalized for selected events, ~50% of them respiratory. Hospitalization rates were 40-50-fold and 2-10-fold higher in those >50 years and with comorbidities, respectively. Our findings suggest that a pragmatic RCT using non-specific endpoints is feasible. However, for outcomes with rates <2.5%, it would require randomization of ~100,000 participants to have the power to detect a rVE difference of ~13%. Targeting selected groups (older adults, those with comorbidities) where frequency of events is high would improve trial efficiency.

Use of Primary Care Data in Research and Pharmacovigilance: Eight Scenarios Where Prescription Data are Absent.

The use of primary care databases has been integral in pharmacoepidemiological studies and pharmacovigilance. Primary care databases derive from electronic health records and offer a comprehensive description of aggregate patient data, from demography to medication history, and good sample sizes. Studies using these databases improve our understanding of prescribing characteristics and associated risk factors to facilitate better patient care, but there are limitations. We describe eight key scenarios where study data outcomes can be affected by absent prescriptions in UK primary care databases: (1) out-of-hours, urgent care and acute care prescriptions; (2) specialist-only prescriptions; (3) alternative community prescribing, such as pharmacy, family planning clinic or sexual health clinic medication prescriptions; (4) newly licensed medication prescriptions; (5) medications that do not require prescriptions; (6) hospital inpatient and outpatient prescriptions; (7) handwritten prescriptions; and (8) private pharmacy and private doctor prescriptions. The significance of each scenario is dependent on the type of medication under investigation, nature of the study and expected outcome measures. We recommend that all researchers using primary care databases be aware of the potential for missing prescribing data and be sensitive to how this can vary substantially between items, drug classes, patient groups and over time. Close liaison with practising primary care clinicians in the UK is often essential to ensure awareness of nuances in clinical practice.

Ability of Primary Care Health Databases to Assess Medicinal Products Discussed by the European Union Pharmacovigilance Risk Assessment Committee.

This study measured the exposure to different categories of medicinal products discussed by the European Union (EU) Pharmacovigilance Risk Assessment Committee from September to November 2018 in four electronic primary care health databases: IQVIA Medical Research Data-UK, IQVIA Medical Research Data-France, IQVIA Medical Research Data-Germany, and Clinical Practice Research Datalink Aurum, in the entire lifespan of each database until August 31, 2018. The assessment of 83 centrally authorized products and 45 nationally authorized products showed that coverage was better for products marketed for longer duration and worse for orphan drugs. The ability to detect associations against hypothetical comparators was better for more common events and for larger effect sizes. Coverage of advanced therapies was worse for those typically administered in a specialized rather than primary care setting. This study shows that to enable better informed regulatory decisions there is a need to access complementary data sources, particularly capturing secondary care prescribing.

Hospitalisation rates and predictors in people with dementia: a systematic review and meta-analysis.

BACKGROUND: Hospitalisation is often harmful for people with dementia and results in high societal costs, so avoidance of unnecessary admissions is a global priority. However, no intervention has yet reduced admissions of community-dwelling people with dementia. We therefore aimed to examine hospitalisation rates of people with dementia and whether these differ from people without dementia and to identify socio-demographic and clinical predictors of hospitalisation. METHODS: We searched MEDLINE, Embase, and PsycINFO from inception to 9 May 2019. We included observational studies which (1) examined community-dwelling people with dementia of any age or dementia subtype, (2) diagnosed dementia using validated diagnostic criteria, and (3) examined all-cause general (i.e. non-psychiatric) hospital admissions. Two authors screened abstracts for inclusion and independently extracted data and assessed included studies for risk of bias. Three authors graded evidence strength using Cochrane's GRADE approach, including assessing for evidence of publication bias using Begg's test. We used random effects meta-analysis to pool estimates for hospitalisation risk in people with and without dementia. RESULTS: We included 34 studies of 277,432 people with dementia: 17 from the USA, 15 from Europe, and 2 from Asia. The pooled relative risk of hospitalisation for people with dementia compared to those without was 1.42 (95% confidence interval 1.21, 1.66) in studies adjusted for age, sex, and physical comorbidity. Hospitalisation rates in people with dementia were between 0.37 and 1.26/person-year in high-quality studies. There was strong evidence that admission is associated with older age, and moderately strong evidence that multimorbidity, polypharmacy, and lower functional ability are associated with admission. There was strong evidence that dementia severity alone is not associated. CONCLUSIONS: People with dementia are more frequently admitted to hospital than those without dementia, independent of physical comorbidities. Future interventions to reduce unnecessary hospitalisations should target potentially modifiable factors, such as polypharmacy and functional ability, in high-risk populations.

Controlling the crystallization of porous organic cages: molecular analogs of isoreticular frameworks using shape-specific directing solvents.

Small structural changes in organic molecules can have a large influence on solid-state crystal packing, and this often thwarts attempts to produce isostructural series of crystalline solids. For metal-organic frameworks and covalent organic frameworks, this has been addressed by using strong, directional intermolecular bonding to create families of isoreticular solids. Here, we show that an organic directing solvent, 1,4-dioxane, has a dominant effect on the lattice energy for a series of organic cage molecules. Inclusion of dioxane directs the crystal packing for these cages away from their lowest-energy polymorphs to form isostructural, 3-dimensional diamondoid pore channels. This is a unique function of the size, chemical function, and geometry of 1,4-dioxane, and hence, a noncovalent auxiliary interaction assumes the role of directional coordination bonding or covalent bonding in extended crystalline frameworks. For a new cage, CC13, a dual, interpenetrating pore structure is formed that doubles the gas uptake and the surface area in the resulting dioxane-directed crystals.