Potentially inappropriate medication use and mortality in patients with cognitive impairment.

PURPOSE: Potentially inappropriate medications (PIMs) are associated with falls, hospitalization, and cognitive decline. Few studies have investigated the association between PIMs related to cognitive impairment (PIMCog) and mortality in dementia or mild cognitive impairment (MCI). METHODS: This was a retrospective observational study. Patients diagnosed with MCI or dementia (DSM-IV criteria) presenting to a tertiary-referral memory clinic from 2013 to 2019 were eligible. The primary outcome was all-cause death. Secondary outcomes were vascular death and non-vascular death. The primary exposure variable of interest was PIMCog, defined as any medication in the Beers 2015 or STOPP criteria, classified as potentially inappropriate for patients with cognitive impairment. Anticholinergic burden was measured using the anticholinergic cognitive burden (ACB) scale. Polypharmacy was defined as ≥ 5 medications. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs). RESULTS: Four hundred eighteen patients were included (n = 261 dementia, n = 157 MCI). The median age was 79 (interquartile range [IQR] 74-82) and median follow-up was 809 days (IQR 552-1571). One or more PIMCog was prescribed in 141 patients (33.4%). PIMCog use was associated with all-cause mortality after adjustment for age, sex, dementia severity, Charlson's Co-morbidity Index, chronic obstructive pulmonary disease, congestive cardiac failure, and peripheral vascular disease (HR 1.96, 95% CI 1.24-3.09). PIMCog use was associated with vascular death (HR 3.28, 95% CI 1.51-7.11) but not with non-vascular death (HR 1.40 95% CI 0.78-2.52). CONCLUSION: PIMCog use in patients with cognitive impairment is high. It is independently associated with all-cause mortality and vascular death. This is a potential modifiable risk factor for death in this patient cohort. Further research is required to independently validate this finding.

Incidence, event rates, and early outcome of stroke in Dublin, Ireland: the North Dublin population stroke study.

BACKGROUND AND PURPOSE: The World Health Organization has emphasized the importance of international population-based data for unbiased surveillance of stroke incidence and outcome. To date, few such studies have been conducted using recommended gold-standard ascertainment methods. We conducted a large, population-based stroke study in Dublin, Ireland. METHODS: Using gold-standard ascertainment methods, individuals with stroke and transient ischemic attack occurring over a 12-month period (December 1, 2005-November 30, 2006) in North Dublin were identified. Disability was assessed using the modified Rankin score and stroke severity (<72 hours) by the National Institutes of Health Stroke Scale. Stroke-related deaths were confirmed by review of medical files, death certificates, pathology, and coroner's records. Crude and standardized (to European and World Health Organization standard populations) rates of incidence, risk factors, severity, and early outcome (mortality, case-fatality, disability) were calculated, assuming a Poisson distribution for the number of events. RESULTS: Seven hundred one patients with new stroke or transient ischemic attack were ascertained (485 first-ever stroke patients, 83 recurrent stroke patients, 133 first-ever transient ischemic attack patients). Crude frequency rates (all rates per 1000 person-years) were: 1.65 (95% CI, 1.5-1.79; first-ever stroke), 0.28 (95% CI, 0.22-0.35; recurrent stroke), and 0.45 (95% CI, 0.37-0.53; first-ever transient ischemic attack). Age-adjusted stroke rates were higher than those in 9 other recent population-based samples from high-income countries. High rates of subtype-specific risk factors were observed (atrial fibrillation, 31.3% and smoking, 29.1% in ischemic stroke; warfarin use, 21.2% in primary intracerebral hemorrhage; smoking, 53.9% in subarachnoid hemorrhage; P<0.01 for all compared with other subtypes). Compared with recent studies, 28-day case-fatality rates for primary intracerebral hemorrhage (41%; 95% CI, 29.2%-54.1%) and subarachnoid hemorrhage (46%; 95% CI, 28.8%-64.5%) were greater in Dublin. CONCLUSIONS: Using gold-standard methods for case ascertainment, we found high incidence rates of stroke in Dublin compared with those in similar high-income countries; this is likely explained in part by high rates of subtype-specific risk factors.

PCR ribotype prevalence and molecular basis of macrolide-lincosamide-streptogramin B (MLSB) and fluoroquinolone resistance in Irish clinical Clostridium difficile isolates.

BACKGROUND: Antimicrobial use is recognized as a risk factor for Clostridium difficile infection (CDI) and outbreaks. We studied the relationship between PCR ribotype, antimicrobial susceptibility and the genetic basis of resistance in response to exposure to antimicrobial agents. METHODS: C. difficile isolates were cultured from 133 CDI patients for whom recent antimicrobial drug exposure had been recorded. Isolates were ribotyped by PCR and assessed for their susceptibility to the macrolide-lincosamide-streptogramin B (MLS(B)) group of compounds (erythromycin and clindamycin) and fluoroquinolone antimicrobials (ciprofloxacin, levofloxacin and moxifloxacin). Where relevant, the genetic basis of resistance was determined. RESULTS: Prevalent ribotypes (including 027, 001 and 106) exhibited significantly greater antimicrobial resistance compared with ribotypes 078 and 014, among others. Clindamycin-resistant ribotype 078 was detected for the first time. Ribotypes 027 and 001 were more likely to exhibit MLS(B) resistance, a feature that was associated with the erm(B) gene. Exposure to MLS(B) or fluoroquinolone antimicrobial compounds in the 8 weeks prior to the onset of infection was not associated with specific genetic markers of resistance. Single amino acid substitutions in the A and B subunits of DNA gyrase were noted and were ribotype specific and linked to resistance to moxifloxacin. CONCLUSIONS: Resistance to MLS(B) and fluoroquinolone antimicrobial compounds is common among prevalent ribotypes of C. difficile. The genetic basis for antimicrobial resistance appears to be ribotype specific and conserved in the absence of recent antimicrobial selection pressure.

The host immune response to Clostridium difficile.

Clostridium difficile is the most common cause of nosocomial bacterial diarrhoea in the Western world. Diarrhoea and colitis are caused by the actions of toxins A and B released by pathogenic strains of C. difficile. Adaptive immune responses to these toxins influence the outcomes of C. difficile infection (CDI). Symptomless carriers of toxinogenic C. difficile and those with a single episode of CDI without recurrence show more robust antitoxin immune responses than those with symptomatic and recurrent disease. Immune-based approaches to CDI therapy and prevention have been developed using active vaccination or passive immunotherapy targeting C. difficile toxins. Innate immune responses to C. difficile and its toxins are also central to the pathophysiology of CDI. An acute intestinal inflammatory response with prominent neutrophil infiltration and associated tissue injury is characteristic of CDI. Furthermore, inhibiting this acute inflammatory response can protect against the intestinal injury that results from exposure to C. difficile toxins in animal models. Studies examining host risk factors for CDI have led to validated clinical prediction tools for risk of primary and of recurrent disease. Risk factors associated with severe CDI with poor clinical outcomes have also been identified and include marked elevation of the peripheral white blood cell count and elevated creatinine. However, further work is needed in this area to guide the clinical application of new approaches to disease prevention and treatment including new antimicrobials as well as passive and active immunization.

Stroke subtype classification to mechanism-specific and undetermined categories by TOAST, A-S-C-O, and causative classification system: direct comparison in the North Dublin population stroke study.

BACKGROUND AND PURPOSE: Reliable etiologic classification of ischemic stroke may enhance clinical trial design and identification of subtype-specific environmental and genetic risk factors. Although new classification systems (Causative Classification System [CCS] and ASCO [A for atherosclerosis, S for small vessel disease, C for cardiac source, O for other cause]) have been developed to improve subtype assignment, few comparative data exist from large studies. We hypothesized that both CCS and ASCO would reduce the proportion of patients classified as cause undetermined compared with the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) scheme in a large population-based stroke study. METHODS: A single rater classified all first-ever ischemic strokes in the North Dublin Population Stroke Study, a population-based study of 294 529 North Dublin residents. Published algorithms for TOAST, CCS, and ASCO were applied. RESULTS: In 381 first-ever ischemic stroke patients, CCS assigned fewer patients as cause undetermined (26.2% versus 39.4%; P<0.000001), with increased assignment of cardio-aortic embolism (relative increase 6.9%; P=0.004), large artery atherosclerosis (relative increase 44.1%; P=0.00006), small artery occlusion (relative increase 27.3%; P=0.00006), and other causes (relative increase 91.7%; P=0.001) compared with TOAST. When ASCO grade 1 evidence was applied, fewer patients were classified as small artery disease (relative decrease 29.1%; P=0.007) and more as large artery/atherothrombotic (relative increase 17.6%; P=0.03). ASCO grade 1 did not reduce the proportion of cause undetermined cases compared with TOAST (42.3% versus 39.4%; P=0.2). Agreement between systems ranged from good (kappa=0.61 for TOAST/ASCO grade 1 small artery category) to excellent (kappa=0.95 for TOAST/CCS and ASCO grade 1/CCS cardio/aorto-embolism category). Application of ASCO grades 1 to 3 indicated evidence of large artery/atherosclerosis (73.3%), cardio-embolism (31.3%), small artery (64.7%), and other cause (12%) in TOAST-undetermined cases. CONCLUSIONS: Both CCS and ASCO schemes showed good-to-excellent agreement with TOAST, but each had specific characteristics compared with TOAST for subtype assignment and data retention. The feasibility of a single combined classification system should be considered.