Streptococcus pneumoniae is a common nasopharyngeal colonizer, but can also cause life-threatening invasive diseases such as empyema, bacteremia and meningitis. Genetic variation of host and pathogen ...is known to play a role in invasive pneumococcal disease, though to what extent is unknown. In a genome-wide association study of human and pathogen we show that human variation explains almost half of variation in susceptibility to pneumococcal meningitis and one-third of variation in severity, identifying variants in CCDC33 associated with susceptibility. Pneumococcal genetic variation explains a large amount of invasive potential (70%), but has no effect on severity. Serotype alone is insufficient to explain invasiveness, suggesting other pneumococcal factors are involved in progression to invasive disease. We identify pneumococcal genes involved in invasiveness including pspC and zmpD, and perform a human-bacteria interaction analysis. These genes are potential candidates for the development of more broadly-acting pneumococcal vaccines.
Low vitamin B-12 concentrations are frequently observed among older adults. Malabsorption is hypothesized to be an important cause of vitamin B-12 inadequacy, but serum vitamin B-12 may also be ...differently affected by vitamin B-12 intake depending on food source. We examined associations between dietary sources of vitamin B-12 (meat, fish and shellfish, eggs, dairy) and serum vitamin B-12, using cross-sectional data of 600 Dutch community-dwelling adults (≥65 years). Dietary intake was assessed with a validated food frequency questionnaire. Vitamin B-12 concentrations were measured in serum. Associations were studied over tertiles of vitamin B-12 intake using P for trend, by calculating prevalence ratios (PRs), and splines. Whereas men had significantly higher vitamin B-12 intakes than women (median (25th-75th percentile): 4.18 (3.29-5.38) versus 3.47 (2.64-4.40) μg/day), serum vitamin B-12 did not differ between the two sexes (mean ± standard deviation (SD): 275 ± 104 pmol/L versus 290 ± 113 pmol/L). Higher intakes of dairy, meat, and fish and shellfish were significantly associated with higher serum vitamin B-12 concentrations, where meat and dairy-predominantly milk were the most potent sources. Egg intake did not significantly contribute to higher serum vitamin B-12 concentrations. Thus, dairy and meat were the most important contributors to serum vitamin B-12, followed by fish and shellfish.
Folic acid and vitamin B12 play key roles in one-carbon metabolism. Disruption of one-carbon metabolism may be involved in the risk of cancer. Our aim was to assess the long-term effect of ...supplementation with both folic acid and vitamin B12 on the incidence of overall cancer and on colorectal cancer in the B Vitamins for the Prevention of Osteoporotic Fractures (B-PROOF) trial.
Long-term follow-up of B-PROOF trial participants (
= 2,524), a multicenter, double-blind randomized placebo-controlled trial designed to assess the effect of 2 to 3 years daily supplementation with folic acid (400 μg) and vitamin B12 (500 μg) versus placebo on fracture incidence. Information on cancer incidence was obtained from the Netherlands cancer registry (Integraal Kankercentrum Nederland), using the International Statistical Classification of Disease (ICD-10) codes C00-C97 for all cancers (except C44 for skin cancer), and C18-C20 for colorectal cancer.
Allocation to B vitamins was associated with a higher risk of overall cancer 171 (13.6%) vs. 143 (11.3%); HR 1.25; 95% confidence interval (CI), 1.00-1.53,
= 0.05. B vitamins were significantly associated with a higher risk of colorectal cancer 43(3.4%) vs. 25(2.0%); HR 1.77; 95% CI, 1.08-2.90,
= 0.02.
Folic acid and vitamin B12 supplementation was associated with an increased risk of colorectal cancer.
Our findings suggest that folic acid and vitamin B12 supplementation may increase the risk of colorectal cancer. Further confirmation in larger studies and in meta-analyses combining both folic acid and vitamin B12 are needed to evaluate whether folic acid and vitamin B12 supplementation should be limited to patients with a known indication, such as a proven deficiency.
Periodontitis is one of the most common inflammatory diseases, with a prevalence of 11% worldwide for the severe forms and an estimated heritability of 50%. The disease is characterized by ...destruction of the alveolar bone due to an aberrant host inflammatory response to a dysbiotic oral microbiome. Previous genome-wide association studies (GWAS) have reported several suggestive susceptibility loci. Here, we conducted a GWAS using a German and Dutch case-control sample of aggressive periodontitis (AgP, 896 cases, 7,104 controls), a rare but highly severe and early-onset form of periodontitis, validated the associations in a German sample of severe forms of the more moderate phenotype chronic periodontitis (CP) (993 cases, 1,419 controls). Positive findings were replicated in a Turkish sample of AgP (223 cases, 564 controls). A locus at SIGLEC5 (sialic acid binding Ig-like lectin 5) and a chromosomal region downstream of the DEFA1A3 locus (defensin alpha 1-3) showed association with both disease phenotypes and were associated with periodontitis at a genome-wide significance level in the pooled samples, with P = 1.09E-08 (rs4284742,-G; OR = 1.34, 95% CI = 1.21-1.48) and P = 5.48E-10 (rs2738058,-T; OR = 1.28, 95% CI = 1.18-1.38), respectively. SIGLEC5 is expressed in various myeloid immune cells and classified as an inhibitory receptor with the potential to mediate tyrosine phosphatases SHP-1/-2 dependent signaling. Alpha defensins are antimicrobial peptides with expression in neutrophils and mucosal surfaces and a role in phagocyte-mediated host defense. This study identifies the first shared genetic risk loci of AgP and CP with genome-wide significance and highlights the role of innate and adaptive immunity in the etiology of periodontitis.
Periodontitis is one of the most common inflammatory diseases, with a prevalence of 11% worldwide for the severe forms and an estimated heritability of 50%. It is classified into the widespread ...moderate form chronic periodontitis (CP) and the rare early-onset and severe phenotype aggressive periodontitis (AgP). These different disease manifestations are thought to share risk alleles and predisposing environmental factors. To obtain novel insights into the shared genetic etiology and the underlying molecular mechanisms of both forms, we performed a two step-wise meta-analysis approach using genome-wide association studies of both phenotypes. Genotypes from imputed genome-wide association studies (GWAS) of AgP and CP comprising 5,095 cases and 9,908 controls of North-West European genetic background were included. Two loci were associated with periodontitis at a genome-wide significance level. They located within the pseudogene MTND1P5 on chromosome 8 (rs16870060-G, P = 3.69 × 10
, OR = 1.36, 95% CI = 1.23-1.51) and intronic of the long intergenic non-coding RNA LOC107984137 on chromosome 16, downstream of the gene SHISA9 (rs729876-T, P = 9.77 × 10
, OR = 1.24, 95% CI = 1.15-1.34). This study identified novel risk loci of periodontitis, adding to the genetic basis of AgP and CP.
Background
Frailty and adverse drug effects are linked in the fact that polypharmacy is correlated with the severity of frailty; however, a causal relation has not been proven in older people with ...clinically manifest frailty.
Methods
A literature search was performed in Medline to detect prospective randomized controlled trials (RCTs) testing the effects of pharmacological interventions or medication optimization in older frail adults on comprehensive frailty scores or partial aspects of frailty that were published from January 1998 to October 2019.
Results
Twenty-five studies were identified, 4 on comprehensive frailty scores and 21 on aspects of frailty. Two trials on comprehensive frailty scores showed positive results on frailty although the contribution of medication review in a multidimensional approach was unclear. In the studies on aspects related to frailty, ten individual drug interventions showed improvement in physical performance, muscle strength or body composition utilizing alfacalcidol, teriparatide, piroxicam, testosterone, recombinant human chorionic gonadotropin, or capromorelin. There were no studies examining negative effects of drugs on frailty.
Conclusion
So far, data on a causal relationship between drugs and frailty are inconclusive or related to single-drug interventions on partial aspects of frailty. There is a clear need for RCTs on this topic that should be based on a comprehensive, internationally consistent and thus reproducible concept of frailty assessment.
Aims
To investigate the association between use of β‐blockers and β‐blocker characteristics – selectivity, lipid solubility, intrinsic sympathetic activity (ISA) and CYP2D6 enzyme metabolism – and ...fall risk.
Methods
Data from two prospective studies were used, including community‐dwelling individuals, n = 7662 (the Rotterdam Study) and 2407 (B‐PROOF), all aged ≥55 years. Fall incidents were recorded prospectively. Time‐varying β‐blocker use was determined using pharmacy dispensing records. Cox proportional hazard models adjusted for age and sex were applied to determine the association between β‐blocker use, their characteristics – selectivity, lipid solubility, ISA and CYP2D6 enzyme metabolism – and fall risk. The results of the studies were combined using meta‐analyses.
Results
In total 2917 participants encountered a fall during a total follow‐up time of 89 529 years. Meta‐analysis indicated no association between use of any β‐blocker, compared to nonuse, and fall risk, hazard ratio (HR) = 0.97 95% confidence interval (CI) 0.88–1.06. Use of a selective β‐blocker was also not associated with fall risk, HR = 0.92 (95%CI 0.83–1.01). Use of a nonselective β‐blocker was associated with an increased fall risk, HR = 1.22 (95%CI 1.01–1.48). Other β‐blocker characteristics including lipid solubility and CYP2D6 enzyme metabolism were not associated with fall risk.
Conclusion
Our study suggests that use of a nonselective β‐blocker, contrary to selective β‐blockers, is associated with an increased fall risk in an older population. In clinical practice, β‐blockers have been shown effective for a variety of cardiovascular indications. However, fall risk should be considered when prescribing a β‐blocker in this age group, and the pros and cons for β‐blocker classes should be taken into consideration.
•This study provides an overview of the use of behavioral theory and UCD in personas-construction for health technology development.•We constructed six personas of a multifactorial falls risk ...assessment tool encompassing external and intrinsic user characteristics.•Personas were highly useful for making decisions about improving the usability and implementation of the tool in practice.•Targeting important external and intrinsic user characteristics that facilitate use and implementation could enhance technology adoption.
Multifactorial falls risk assessment tools (FRATs) can be an effective falls prevention method for older adults, but are often underutilized by health care professionals (HCPs). This study aims to enhance the use and implementation of multifactorial FRATs by combining behavioral theory with the user-centered design (UCD) method of personas construction. Specifically, the study aimed to (1) construct personas that are based on external (i.e., needs, preferences) and intrinsic user characteristics (i.e., behavioral determinants); and (2) use these insights to inform requirements for optimizing an existing Dutch multifactorial FRAT (i.e., the ‘Valanalyse’).
Survey data from HCPs (n = 31) was used to construct personas of the ‘Valanalyse.’ To examine differences between clusters on 68 clustering variables, a multivariate cluster analysis technique with non-parametric analyses and computational methods was used. The aggregated external and intrinsic user characteristics of personas were used to inform key design and implementation requirements for the ‘Valanalyse,’ respectively, whereby intrinsic user characteristics were matched with appropriate behavior change techniques to guide implementation.
Significant differences between clusters were observed in 20 clustering variables (e.g., behavioral beliefs, situations for use). These variables were used to construct six personas representing users of each cluster. Together, the six personas helped operationalize four key design requirements (e.g., guide treatment-related decision making) and 14 implementation strategies (e.g., planning coping responses) for optimizing the ‘Valanalyse’ in Dutch geriatric, primary care settings.
The findings suggest that theory- and evidence-based personas that encompass both external and intrinsic user characteristics are a useful method for understanding how the use and implementation of multifactorial FRATs can be optimized with and for HCPs, providing important implications for developers and eHealth interventions with regards to encouraging technology adoption.
To investigate the effect of withdrawal of fall-risk-increasing-drugs (FRIDs) versus ‘care as usual’ on reducing falls in community-dwelling older fallers.
Randomised multicentre trial
Six hundred ...and twelve older adults who visited an Emergency Department (ED) because of a fall.
Withdrawal of FRIDs.
Primary outcome was time to the first self-reported fall. Secondary outcomes were time to the second self-reported fall and to falls requiring a general practitioner (GP)-consultation or ED-visit. Intention-to-treat (primary) and a per-protocol (secondary) analysis were conducted. The hazard ratios (HRs) for time-to-fall were calculated using a Cox-regression model. Differences in cumulative incidence of falls were analysed using Poisson regression.
During 12 months follow-up, 91 (34%) control and 115 (37%) intervention participants experienced a fall; 35% of all attempted interventions were unsuccessful, either due to recurrence of the initial indication for prescribing, additional medication for newly diagnosed conditions or non-compliance. Compared to baseline, the overall percentage of users of ≥3 FRIDs at 12 months did not change in either the intervention or the control group. Our intervention did not have a significant effect on time to first fall (HR 1.17; 95% confidence interval 0.89–1.54), time to second fall (1.19; 0.78–1.82), time to first fall-related GP-consultation (0.66; 0.42–1.06) or time to first fall-related ED-visit (0.85; 0.43–1.68).
In this population of complex multimorbid patients visiting an ED because of a fall, our single intervention of FRIDs-withdrawal was not effective in reducing falls.
Netherlands Trial Register NTR1593.
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