Cardiovascular and lifestyle risk factors of mild cognitive impairment in UK veterans and non-veterans.

BACKGROUND: The link between poor cardiovascular health (CVH), lifestyle and mild cognitive impairment (MCI) has been well established in the general population. However, there is limited research exploring these associations in ageing UK veterans. AIMS: This study explored the risk of MCI and its association with nine CVH and lifestyle risk factors (including diabetes, heart disease, high cholesterol, high blood pressure, obesity, stroke, physical inactivity, the frequency of alcohol consumption and smoking) in UK veterans and non-veterans. METHODS: This prospective cohort study comprised data from the PROTECT study between 2014 and 2022. Participants comprised of UK military veterans and non-veterans aged ≥50 years at baseline. Veteran status was defined using the Military Service History Questionnaire. CVH and lifestyle risk factors were defined using a combination of self-report measures, medication history or physical measurements. MCI was defined as the presence of subjective and objective cognitive impairment. RESULTS: Based on a sample of 9378 veterans (n = 488) and non-veterans (n = 8890), the findings showed the risk of MCI significantly reduced in veterans with obesity, those who frequently consumed alcohol and were physically inactive compared to non-veterans. The risk of MCI significantly increased in veterans with diabetes (hazards ratio [HR] = 2.22, 95% confidence interval [CI] 1.04-4.75, P ≤ 0.05) or high cholesterol (HR = 3.11, 95% CI 1.64-5.87, P ≤ 0.05) compared to veterans without. CONCLUSIONS: This study identified CVH and lifestyle factors of MCI in UK veterans and non-veterans. Further work is needed to understand these associations and the underpinning mechanisms which could determine intervention strategies to reduce the risk of MCI.

Rumination moderates the longitudinal associations of awareness of age-related change with depressive and anxiety symptoms.

OBJECTIVE: Lower awareness of age-related gains (AARC-gains) and higher awareness of age-related losses (AARC-losses) may be risk factors for depressive and anxiety symptoms. We explored whether: (1) Baseline AARC-gains and AARC-losses predict depressive and anxiety symptoms at one-year follow-up; (2) age and rumination moderate these associations; (3) levels of AARC-gains and AARC-losses differ among individuals with different combinations of current and past depression and/or with different combinations of current and past anxiety. METHODS: In this one-year longitudinal cohort study participants (N = 3386; mean age = 66.0; SD = 6.93) completed measures of AARC-gains, AARC-losses, rumination, depression, anxiety, and lifetime diagnosis of depression and anxiety in 2019 and 2020. Regression models with tests of interaction were used. RESULTS: Higher AARC-losses, but not lower AARC-gains, predicted more depressive and anxiety symptoms. Age did not moderate these associations. Associations of lower AARC-gains and higher AARC-losses with more depressive symptoms and of higher AARC-losses with more anxiety symptoms were stronger in those with higher rumination. Individuals with both current and past depression reported highest AARC-losses and lowest AARC-gains. Those with current, but not past anxiety, reported highest AARC-losses. CONCLUSION: Perceiving many age-related losses may place individuals at risk of depressive and anxiety symptoms, especially those who frequently ruminate.

Influence of fiber degradability of corn silage in diets with lower and higher fiber content on lactational performance, nutrient digestibility, and ruminal characteristics in lactating Holstein cows.

The effect of neutral detergent fiber (NDF) degradability of corn silage in diets containing lower and higher NDF concentrations on lactational performance, nutrient digestibility, and ruminal characteristics in lactating Holstein cows was measured. Eight ruminally cannulated Holstein cows averaging 91 ± 4 (standard error) days in milk were used in a replicated 4 × 4 Latin square design with 21-d periods (7-d collection periods). Dietary treatments were formulated to contain either conventional (CON; 48.6% 24-h NDF degradability; NDFD) or brown midrib-3 (BM3; 61.1% 24-h NDFD) corn silage and either lower NDF (LNDF) or higher NDF (HNDF) concentration (32.0 and 35.8% of ration dry matter, DM) by adjusting the dietary forage content (52 and 67% forage, DM basis). The dietary treatments were (1) CON-LNDF, (2) CON-HNDF, (3) BM3-LNDF, and (4) BM3-HNDF. Data were analyzed as a factorial arrangement of diets within a replicated Latin square design with the MIXED procedure of SAS (SAS Institute Inc., Cary, NC) with fixed effects of NDFD, NDF, NDFD × NDF, period(square), and square. Cow within square was the random effect. Time and its interactions with NDFD and NDF were included in the model when appropriate. An interaction between NDFD and NDF content resulted in the HNDF diet decreasing dry matter intake (DMI) with CON corn silage but not with BM3 silage. Cows fed the BM3 corn silage had higher DMI than cows fed the CON corn silage, whereas cows fed the HNDF diet consumed less DM than cows fed the LNDF diet. Cows fed the BM3 diets had greater energy-corrected milk yield, higher milk true protein content, and lower milk urea nitrogen concentration than cows fed CON diets. Additionally, cows fed the BM3 diets had greater total-tract digestibility of organic matter and NDF than cows fed the CON diets. Compared with CON diets, the BMR diets accelerated ruminal NDF turnover. When incorporated into higher NDF diets, corn silage with greater in vitro 24-h NDFD and lower undegradable NDF at 240 h of in vitro fermentation (uNDF240) allowed for greater DMI intake than CON. In contrast, for lower NDF diets, NDFD of corn silage did not affect DMI, which suggests that a threshold level of inclusion of higher NDFD corn silage is necessary to observe enhanced lactational performance. Results suggest that there is a maximum gut fill of dietary uNDF240 and that higher NDFD corn silage can be fed at greater dietary concentrations.

Evaluation of source of corn silage and trace minerals on rumen characteristics and passage rate of Holstein cows.

The effects of source of corn silage and trace mineral on rumen fermentation, turnover, and particle passage rates were evaluated with 8 ruminally cannulated Holstein cows averaging 83 (standard error = 5) days in milk in a replicated 4 × 4 Latin square design with a 2 × 2 factorial arrangement of treatments and 28-d periods. The diets consisted (dry basis) of 55% conventional (CON) or brown midrib-3 (BM3) corn silage, 2% chopped wheat straw, and 43% grain mix with either sulfate (STM) or hydroxy (HTM) source of Cu, Zn, and Mn trace minerals. The targeted supplemental amount of Cu, Zn, and Mn was 194, 1,657, and 687 mg/d, respectively. The dietary treatments were (1) CON-STM, (2) CON-HTM, (3) BM3-STM, and (4) BM3-HTM. Dietary nutrient composition of BM3 diets averaged 32.1% amylase neutral detergent fiber on an organic matter basis (aNDFom) and 6.9% undigested neutral detergent fiber at 240 h of in vitro fermentation (uNDF240om; % of dry matter), and CON diets averaged 36.2% aNDFom and 8.6% uNDF240om (% of dry matter). Data were summarized by period and analyzed as a replicated Latin square design with fixed model effects for corn silage, trace mineral, corn silage and trace mineral interaction, period within replicated square, and replicated square using the MIXED procedure of SAS (version 9.4, SAS Institute Inc., Cary, NC). Cow within replicate was a random effect. Daily mean, standard deviation, minimum, and maximum for rumen pH were unaffected by corn silage or trace mineral source. Cows fed the CON diets had greater rumen acetate percentage than cows fed the BM3 diets (65.7 vs. 64.7 molar %). In contrast, cows fed the BM3 diets had greater rumen propionate percentage than cows fed the CON diets (21.4 vs. 20.4 molar %). Total volatile fatty acid concentration was lower for cows fed STM versus HTM in BM3 diets, but not for the cows fed the CON diets. Cows fed the BM3 diets had faster turnover rate and shorter turnover time for uNDF240om than cows fed the CON diets (3.12 vs. 2.86%/h and 33.3 vs. 36.5 h, respectively). Cows fed the BM3 diets had a faster passage rate of small and medium corn silage neutral detergent fiber particles than cows fed the CON diets (5.73 vs. 5.37%/h and 4.74 vs. 4.31%/h, respectively). We observed a corn silage by source of trace mineral interaction on organic matter and uNDF240om rumen pool size and organic matter turnover. Overall, source of corn silage had a pronounced influence on rumen dynamics presumably related to greater in vitro neutral detergent fiber digestibility and lower uNDF240om content of BM3 corn silage that allowed for faster turnover of indigestible neutral detergent fiber and greater passage rate of corn silage particles. In contrast, the source of trace mineral had much less significant effects on rumen fermentation, turnover, and particle passage rates. Corn silage-based diets intended to enhance rumen fiber fermentation, turnover, and passage are more affected by source and digestibility of neutral detergent fiber than source of dietary trace minerals.

Evaluation of source of corn silage and trace minerals on lactational performance and total-tract nutrient digestibility in Holstein cows.

We evaluated the effects of source of corn silage and trace minerals on lactational performance and total-tract digestibility (TTD) of nutrients in 16 Holstein cows averaging 82 (standard error = 3) days in milk in a replicated 4 × 4 Latin square design with a 2 × 2 factorial arrangement of treatments with 28-d periods. The diets consisted [dry matter (DM) basis] of 55% conventional (CON) or brown midrib-3 (BM3) corn silage, 2% chopped wheat straw, and 43% grain mix with either sulfate (STM) or hydroxy (HTM) sources of copper, manganese, and zinc trace minerals. The targeted supplemental concentrations of copper, zinc, and manganese were 194, 1,657, and 687 mg/d, respectively. The dietary treatments were CON-STM, CON-HTM, BM3-STM, and BM3-HTM. The dietary nutrient composition of the BM3 diets averaged 32.1% amylase neutral detergent fiber on an organic matter basis (aNDFom) and 6.9% undigested neutral detergent fiber at 240 h (uNDF240om; % of DM), and CON diets averaged 36.2% aNDFom and 8.6% uNDF240om (% of DM). The average supplemental concentrations of copper, zinc, and manganese for the STM diets were 10, 41, and 64 mg/kg, respectively, and the average supplemental concentrations of copper, zinc, and manganese for the HTM diets were 10, 40, and 62 mg/kg, respectively. The average total dietary concentrations of copper, zinc, and manganese for the STM diets were 17, 104, and 60 mg/kg, respectively, and the average total dietary concentrations of copper, zinc, and manganese for the HTM diets were 17, 91, and 66 mg/kg, respectively. Data were summarized by period and analyzed as a replicated Latin square design with fixed model effects for corn silage, trace minerals, corn silage × trace mineral interaction, period within replicated square, and replicated square using the MIXED procedure of SAS. Cow within replicated square was a random effect. Cows fed the BM3 diets had greater dry matter intake (DMI) and milk yield (28.1 and 47.0 kg/d) than cows fed the CON diets (27.5 and 44.7 kg/d). We found no significant interaction between corn silage and trace minerals for DMI and milk yield. Cows fed the HTM diets (28.1 kg/d) had a greater DMI than cows fed the STM diets (27.5 kg/d). Cows fed the BM3 diets had greater TTD of DM and OM (72.8 and 74.1% of DM) than cows fed the CON diets (71.1 and 72.3% of DM). Cows fed the HTM diets had a tendency for greater TTD of aNDFom than cows fed the STM diets (56.8 vs. 54.9% of DM). Cows fed the CON diets ruminated longer during the day than cows fed the BM3 diets (524 vs. 496 min/d). Corn silage with greater NDF digestibility and lower uNDF240om enhanced DMI, milk yield, and TTD of DM and OM, and hydroxy trace minerals improved DMI and tended to improve TTD of aNDFom. The source of corn silage and trace minerals should be taken into consideration when formulating diets for high-producing dairy cows.

Influence of a novel bm3 corn silage hybrid with floury kernel genetics on lactational performance and feed efficiency of Holstein cows.

Dry matter intake, lactation performance, and chewing behavior of multiparous Holstein cows (n = 15) fed diets containing a novel bm3 corn silage hybrid with floury kernel genetics were compared with cows fed diets containing commercially available conventional and bm3 hybrids using a replicated 3 × 3 Latin square design with 28-d periods. Cows were housed in tiestalls, milked 3 times/d, and fed a total mixed ration containing 49.0% (dry matter basis) of (1) a conventional corn silage hybrid (CONV); (2) a brown midrib bm3 hybrid (BMR); or (3) a bm3 hybrid with floury kernel genetics (BMRFL). All diets contained 6.3% hay crop silage and 44.7% concentrate. Dietary nutrient composition averaged 32.7% neutral detergent fiber (NDF) and 26.3 starch (% of dry matter). Data were analyzed by ANOVA using the MIXED procedure in SAS (SAS Institute Inc., Cary, NC). The dry matter intake was greater for cows fed BMR (28.0 kg/d) compared with CONV (26.8 kg/d), whereas dry matter intake for cows fed BMRFL was intermediate (27.6 kg/d). Energy-corrected milk (ECM) yield was greater for cows fed BMR (50.3 kg/d) and BMRFL (51.8 kg/d) compared with CONV (47.2 kg/d). Milk fat yield was higher for cows fed BMRFL (1.87 kg/d) compared with CONV (1.74 kg/d) and BMR (1.80 kg/d). Milk protein yield was greater for cows fed BMR (1.49 kg/d) and BMRFL (1.54 kg/d) compared with CONV (1.36 kg/d). Milk urea-N was reduced for cows fed BMR (11.61 mg/dL) and BMRFL (11.16 mg/dL) compared with CONV (13.60 mg/dL). Feed efficiency (ECM/dry matter intake) was higher for cows fed BMRFL (1.87) compared with CONV (1.76) and BMR (1.79). Milk N efficiency was greatest for cows fed BMRFL (40.4%) followed by BMR (38.1%) and finally CONV (35.3%). Cows fed CONV chewed 5 min more per kilograms of NDF consumed than cows fed either of the BMR hybrids. No differences were observed among diets in apparent total-tract digestibility of NDF (58.1%) or starch (99.3%). Overall lactational performance was enhanced for cows fed diets containing both BMR and BMRFL hybrids versus CONV. In addition, feeding the BMRFL corn silage improved efficiency of component-corrected milk production and milk N efficiency compared with the CONV and BMR silages.

Evaluation of powdered 0.5% chlorhexidine acetate-based postmilking teat dip compared with a foamed 1% iodine-based postmilking teat dip under cold weather conditions in northern New York.

The objective of this trial was to compare a powdered 0.5% chlorhexidine acetate-based postmilking teat dip with a foamed 1% iodine-based postmilk teat dip during winter on clinical mastitis, subclinical mastitis (somatic cell count ≥200,000 cells/mL), linear score, teat skin condition, teat end score for hyperkeratosis, and risk of developing a new intramammary infection (IMI). Holstein cows (n = 331) housed in freestall and tiestall barns on one farm were blocked by pen, parity, lactation stage, and lactation performance. They were assigned randomly to a powdered chlorhexidine postmilking teat dip (PD; Derma Soft n' Dry, IBA Inc., Millbury, MA) or a foamed iodine-based postmilking teat dip (ID; FS-103, IBA Inc.). Treatments were applied for 6 wk starting January 4, 2016, for 3 milkings per day. Milk samples were collected from each quarter at the beginning and end of the trial and analyzed for aerobic culture and somatic cell count. Cows that had a clinical mastitis event during the trial were quarter sampled for aerobic culture at the time of clinical event. Teat skin condition and teat end score for hyperkeratosis were evaluated at the beginning, middle, and end of the trial based on a 3- and 5-point scale, respectively. No treatment difference was observed for linear score or teat skin condition. Teat end score was greater for ID cows compared with PD cows (2.72 vs. 2.77) at the conclusion of the trial. At the beginning of trial 102 PD quarters and 129 ID quarters had an IMI identified on aerobic culture, 402 PD and 457 ID quarters cultured negative, and 109 PD and 125 ID samples were classified as "no significant growth." At the conclusion of the trial, 129 PD and 101 ID quarters had an IMI. Use of PD resulted in a greater risk for developing a new IMI, based on bacteriological culture, at the conclusion of the trial as compared with ID (relative risk = 1.51; confidence interval: 1.10-2.07). Additionally, use of PD resulted in a greater risk as compared with ID of coagulase-negative staphylococci (relative risk = 1.5; confidence interval: 1.10-2.25) and Staphylococccus aureus (relative risk = 2.30; confidence interval: 1.04-5.07) to be present at the conclusion of the trial. In conclusion, use of PD led to a lower teat end score, an increase in new IMI, and an increased risk of coagulase-negative staphylococci and Staph. aureus compared with ID after 6 wk of product use.

Online assessment of risk factors for dementia and cognitive function in healthy adults.

OBJECTIVE: Several potentially modifiable risk factors for cognitive decline and dementia have been identified, including low educational attainment, smoking, diabetes, physical inactivity, hypertension, midlife obesity, depression, and perceived social isolation. Managing these risk factors in late midlife and older age may help reduce the risk of dementia; however, it is unclear whether these factors also relate to cognitive performance in older individuals without dementia. METHOD: Data from 14 201 non-demented individuals aged >50 years who enrolled in the online PROTECT study were used to examine the relationship between cognitive function and known modifiable risk factors for dementia. Multivariate regression analyses were conducted on 4 cognitive outcomes assessing verbal and spatial working memory, visual episodic memory, and verbal reasoning. RESULTS: Increasing age was associated with reduced performance across all tasks. Higher educational achievement, the presence of a close confiding relationship, and moderate alcohol intake were associated with benefits across all 4 cognitive tasks, and exercise was associated with better performance on verbal reasoning and verbal working memory tasks. A diagnosis of depression was negatively associated with performance on visual episodic memory and working memory tasks, whereas being underweight negatively affected performance on all tasks apart from verbal working memory. A history of stroke was negatively associated with verbal reasoning and working memory performance. CONCLUSION: Known modifiable risk factors for dementia are associated with cognitive performance in non-demented individuals in late midlife and older age. This provides further support for public health interventions that seek to manage these risk factors across the lifespan.

Hematopoietic knockdown of PPARδ reduces atherosclerosis in LDLR-/- mice.

PPARδ (peroxisome proliferator-activated receptor δ) mediates inflammation in response to lipid accumulation. Systemic administration of a PPARδ agonist can ameliorate atherosclerosis. Paradoxically, genetic deletion of PPARδ in hematopoietic cells led to a reduction of atherosclerosis in murine models, suggesting that downregulation of PPARδ expression in these cells may mitigate atherogenesis. To advance this finding forward to potential clinical translation through hematopoietic stem cell transplantation-based gene therapy, we employed a microRNA (miRNA) approach to knock down PPARδ expression in bone marrow cells followed by transplantation of the cells into LDLR-/- mice. We found that knockdown of PPARδ expression in the hematopoietic system caused a dramatic reduction in aortic atherosclerotic lesions. In macrophages, a key component in atherogenesis, knockdown of PPARδ led to decreased expression of multiple pro-inflammatory factors, including monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-1ß and IL-6. Expression of CCR2, a receptor for MCP-1, was also decreased. The downregulation of pro-inflammatory factors is consistent with significant reduction of macrophage presence in the lesions, which may also be attributable to elevation of ABCA1 (ATP-binding cassette, subfamily A, member 1) and depression of adipocyte differentiate-related protein. Furthermore, the abundance of both MCP-1 and matrix metalloproteinase-9 proteins was reduced in plaque areas. Our results demonstrate that miRNA-mediated PPARδ knockdown in hematopoietic cells is able to ameliorate atherosclerosis.

Antidepressants and mortality risk in a dementia cohort: data from SveDem, the Swedish Dementia Registry.

BACKGROUND: The association between mortality risk and use of antidepressants in people with dementia is unknown. OBJECTIVE: To describe the use of antidepressants in people with different dementia diagnoses and to explore mortality risk associated with use of antidepressants 3 years before a dementia diagnosis. METHODS: Study population included 20 050 memory clinic patients from the Swedish Dementia Registry (SveDem) diagnosed with incident dementia. Data on antidepressants dispensed at the time of dementia diagnosis and during 3-year period before dementia diagnosis were obtained from the Swedish Prescribed Drug Register. Cox regression models were used. RESULTS: During a median follow-up of 2 years from dementia diagnosis, 25.8% of dementia patients died. A quarter (25.0%) of patients were on antidepressants at the time of dementia diagnosis, while 21.6% used antidepressants at some point during a 3-year period before a dementia diagnosis. Use of antidepressant treatment for 3 consecutive years before a dementia diagnosis was associated with a lower mortality risk for all dementia disorders and in Alzheimer's disease. CONCLUSION: Antidepressant treatment is common among patients with dementia. Use of antidepressants during prodromal stages may reduce mortality in dementia and specifically in Alzheimer's disease.

Short communication: Effect of on-farm feeding practices on rumen protected lysine products.

Two independent studies were conducted to determine whether mechanical mixing of total mixed ration (TMR) or TMR dry matter alters Lys release from 6 rumen-protected Lys (RPL) products (A, B, C, D, E, and F). In the first study, routine mixing procedures were simulated to determine if inclusion of RPL products in TMR altered in situ release of Lys. Following mixing, Dacron bags containing RPL products were ruminally incubated for 0, 6, 12, or 24 h to determine Lys release. The second study occurred independently of the first, in which Lys release from RPL products was evaluated when incorporated into a TMR that differed in dry matter (DM) content. Bags containing TMR and RPL product mixture were stored at room temperature for 0, 6, 18, and 24 h to simulate RPL product exposure to TMR when mixed and delivered once per day. Concentration of free Lys in both studies was determined using ultra-performance liquid chromatography. Following mechanical mixing, ruminal Lys release was significantly greater for C and tended to increase for F. Mechanical mixing did not alter ruminal Lys release from other RPL products evaluated. Hours of ruminal incubation significantly altered Lys release for all products evaluated, and a significant interaction of mechanical mixing and hours of ruminal incubation was observed for A and C. Exposure to lower TMR DM (40.5 versus 51.8%) significantly increased Lys release from B but did not alter Lys release from the other RPL products evaluated. Moreover, time of exposure to TMR significantly increased Lys release from all RPL products evaluated, and a significant interaction of TMR DM and time of exposure to TMR was observed for B and E. These data suggest mechanical mixing and variation in TMR DM may compromise the rumen protection of RPL products; therefore, on-farm feeding practices may alter efficacy of RPL products in dairy rations.

Health economic evaluation of treatments for Alzheimer's disease: impact of new diagnostic criteria.

The socio-economic impact of Alzheimer's disease (AD) and other dementias is enormous, and the potential economic challenges ahead are clear given the projected future numbers of individuals with these conditions. Because of the high prevalence and cost of dementia, it is very important to assess any intervention from a cost-effectiveness viewpoint. The diagnostic criteria for preclinical AD suggested by the National Institute on Aging and Alzheimer's Association workgroups in combination with the goal of effective disease-modifying treatment (DMT) are, however, a challenge for clinical practice and for the design of clinical trials. Key issues for future cost-effectiveness studies include the following: (i) the consequences for patients if diagnosis is shifted from AD-dementia to predementia states, (ii) bridging the gap between clinical trial populations and patients treated in clinical practice, (iii) translation of clinical trial end-points into measures that are meaningful to patients and policymakers/payers and (iv) how to measure long-term effects. To improve cost-effectiveness studies, long-term population-based data on disease progression, costs and outcomes in clinical practice are needed not only in dementia but also in predementia states. Reliable surrogate end-points in clinical trials that are sensitive to detect effects even in predementia states are also essential as well as robust and validated modelling methods from predementia states that also take into account comorbidities and age. Finally, the ethical consequences of early diagnosis should be considered.

Efficacy of pain treatment on mood syndrome in patients with dementia: a randomized clinical trial.

BACKGROUND: Depression is common in nursing home (NH) patients with dementia, and often clustered with anxiety and other mood symptoms. An association between pain and depressive symptoms has been reported, but the impact of pain management on depression and other mood symptoms has not been investigated. OBJECTIVE: Secondary analyses of a cluster randomized clinical trial examine the response of dementia-related mood symptoms to a Stepwise Protocol of Treating Pain. METHOD: Three-hundred fifty-two patients with moderate and severe dementia and significant behavioural disturbances, related to 60 clusters (i.e. clusters defined as single independent NH units) in 18 NHs of Western Norway, were included. All patients in the intervention group received individual daily pain treatment with paracetamol, extended release morphine, buprenorphine transdermal patch or pregabaline for 8 weeks, with additional follow-up assessment 4 weeks after completion of the intervention. Clusters randomized to control received usual treatment. A mood cluster consisting of depression, anxiety, sleep disorders, apathy and appetite items from the Neuropsychiatric Inventory-Nursing Home (NPI-NH) was the primary outcome. RESULTS: Analysed by Mann-Whitney U-tests, Stepwise Protocol of Treating Pain conferred significant benefit in treatment of the NPI-NH mood cluster (F = 13.4, df = 1;299, p < 0.001) and depression (F = 2.0, df = 1;301, p = 0.025). Further analyses highlighted improvements in apathy (F = 5.3, df = 1;300, p = 0.017), night-time behaviours (F = 3.1, df = 1;301, p = 0.050), and appetite items (F = 11.6, df = 1;301, p = 0.005), but not irritability (p = 0.092) and anxiety (p = 0.125). CONCLUSION: Mood symptoms including depression significantly improved with pain treatment, emphasizing the importance of more rigorous treatment of pain in agitated people with dementia. Findings have potentially immediate clinical relevance.

Associations between risk of mortality and atypical antipsychotic use in vascular dementia: a clinical cohort study.

OBJECTIVES: People with vascular dementia (VaD) are frequently prescribed atypical antipsychotics to treat behavioural and psychological symptoms, but there is an alarming lack of evidence regarding their safety or efficacy in VaD. This study sought to identify the mortality risk associated with the most commonly prescribed atypical antipsychotics in people with VaD compared with people not exposed to these drugs. METHODS: A clinical cohort study of 1531 people with VaD performed using anonymised versions of full electronic health records from the Clinical Record Interactive Search application at the South London and Maudsley NHS Foundation Trust. Patients were identified from 2007 to 2010, of whom 337 were exposed to quetiapine, risperidone or olanzapine. The main outcome measure was mortality. RESULTS: Patients exposed to atypical antipsychotics were not at increased risk of mortality [hazard ratio (HR) 1.05, 95% confidence interval (CI): 0.87-1.26]. Exposure to risperidone did not result in an increased risk of mortality (HR = 0.85; 95% CI: 0.59-1.24), and patients exposed to quetiapine had a non-significant numerical increase in mortality risk (HR = 1.14; 95% CI: 0.93-1.39; p-value = 0.20) compared with untreated patients. Too few patients were exposed to olanzapine alone to provide reliable results. CONCLUSIONS: The absence of a significant increase in mortality risk associated with atypical antipsychotics in people with VaD indicates that a clinical trial of antipsychotics focussing on the treatment of aggression and agitation in this patient group will be justified and feasible following further consideration of possible confounders, which will be critical to determine the role of antipsychotics in treatment of VaD.

CTAD Task Force Paper: Neuropsychiatric Symptoms in AD: Clinical Trials Targeting Mild Behavioral Impairment: A Report from the International CTAD Task Force.

The International CTAD Task Force (TF) addressed challenges related to designing clinical trials for agitation in dementia, presenting accomplishments from the two previous TFs on neuropsychiatric symptoms (NPS). In addition, this TF proposed a paradigm shift in NPS assessment and management, presenting Mild Behavioral Impairment (MBI) as a clinical syndrome. MBI is marked by later-life emergent and persistent NPS in dementia-free older persons (ranging from cognitively unimpaired to subjective cognitive decline to mild cognitive impairment), which facilitates earlier detection and better prognostication of Alzheimer's disease (AD). The TF has made the following recommendations for incorporation of NPS into AD preventative trials: (1) clinical trials targeting improvement in MBI symptoms should be undertaken; (2) treatment trials for MBI should be disease specific and confirm the diagnosis of participants using biomarkers; trials should include measures sensitive to cognitive changes in preclinical AD, which can serve as outcome measures, in addition to changes in biomarker levels; (3) as a first step, pharmacotherapeutic trials should address the full MBI complex as well as the specific symptoms/domains that constitute MBI; (4) clinical trials using problem-adaptation psychotherapy to target affective MBI should be considered; and (5) MBI should be considered in AD trials of disease modifying therapies. The well-validated and widely-used MBI Checklist (MBI-C) is an appropriate symptom rating scale for these studies, as it was developed specifically to identify and measure MBI in dementia-free persons. Other scales such as the Neuropsychiatric Inventory (NPI) may be used, although administration at two timepoints may be necessary to operationalize the MBI criterion of symptom persistence.

Sensitivity of Mycobacterium avium subsp paratuberculosis, Escherichia coli and Salmonella enterica serotype Typhimurium to low pH, high organic acids and ensiling.

AIMS: To evaluate the persistence of Mycobacterium avium subsp paratuberculosis (Myco. paratuberculosis), Salmonella enterica serotype Typhimurium (Salm.Typhimurium) and a commensal Escherichia coli (E. coli) isolate under the low pH and high organic acid (OA) conditions of ensiling of forages. METHODS AND RESULTS: Decay rates and the time required to obtain a 90% reduction in cell concentration were calculated following (i) exposure to buffered OA (pH 4.0, 5.0, 6.0 or 7.0) (ii) exposure to silage exudates and (iii) survival through ensiling of forage materials. Salm. Typhimurium had higher decay rates in silage exudates (-0.5601 day(-1) ) than did E. coli (-0.1265 day(-1) ), but both exhibited lower decay rates in silage than in OA or silage exudates. Myco. paratuberculosis showed no decrease in silage and decay rates in silage exudates were significantly lower (2-12 times) than for the other two organisms. CONCLUSIONS: Escherichia coli, Salm. Typhimurium and Myco. paratuberculosis exhibit marked differences in response to acidity. All three organisms show acid resistance, but Myco. paratuberculosis in particular, if present in manure and applied to forage grasses, may survive the low pH and high OA of the ensilaging process; silage may therefore be a potential route of infection if ingested by a susceptible animal. SIGNIFICANCE AND IMPACT OF STUDY: This information contributes to the understanding of potential risks associated with silage preservation and contamination of livestock feed with manure-borne pathogens.

Increased neural progenitors in individuals with cerebral small vessel disease.

AIMS: Recent work has highlighted a significant increase of neural stem/progenitor cells after stroke in humans. In this study, we examined neurogenesis in small vessel disease, a key concurrent pathology in Alzheimer's disease. METHODS: We assayed autopsy tissue from 13 vascular dementia patients with small vessel disease and 12 age-matched subjects without cerebrovascular pathology, undertaking immunohistochemistry in the affected brain area and the subventricular zone with a well-characterized battery of antibodies to detect neural stem cells/progenitors and immature neurones, as well as choline acetyltransferase immunoreactivity. RESULTS: We showed significant increases ranging from 33% to 92% (P < 0.05) in neural progenitor cells around the areas of microvascular pathology and in the subventricular zone in patients with small vessel disease compared to individuals without cerebrovascular changes, even in patients with severe cerebrovascular disease, as defined by neuropathological assessment. Some of the progenitor cells give rise to immature neurones in the affected areas. These alterations were associated with vascular changes, but were unrelated to the cholinergic deficit observed in the cortex and subventricular zone in these patients, in contrast to other dementias examined such as dementia with Lewy bodies. CONCLUSIONS: This study provides evidence for neurogenesis in small vessel disease and may have important implications for the development of new therapies for neurodegenerative diseases.

Neuropsychiatric symptoms in mild dementia with lewy bodies and Alzheimer's disease.

BACKGROUND/AIMS: To compare neuropsychiatric symptoms in patients with Alzheimer's disease (AD) and dementia with Lewy bodies(DLB). METHODS: Neuropsychiatric symptoms and caregiver distress were assessed using the Neuropsychiatric Inventory (NPI) in mild DLB (n = 57) and AD (n = 126), and compared across the two groups using non-parametric tests. RESULTS: The DLB patients had a higher NPI totalscore (median 24 vs. 11.5, p < 0.005), more numerous symptoms (median 5 vs. 4, p = 0.001) and more clinically significant symptoms (3 vs. 1, p = 0.001). They also had higher item hallucinations (6 vs. 2, p < 0.005) and apathy (7 vs. 5, p = 0.002) subscores. Caregivers scored higher on the NPI total caregiver distress scale (12.5 vs. 6, p = 0.003). CONCLUSIONS: In mild dementia, DLB patients have more neuropsychiatric symptoms and more associated caregiver distress compared with AD.

Clinical trials of dementia with Lewy bodies and Parkinson's disease dementia.

Despite the frequency and importance of dementia associated with Parkinson's disease (PDD) and dementia with Lewy bodies (DLB), there is relatively little evidence on which to base treatment. Evidence from meta-analysis suggests that rivastigmine can improve cognition and functioning in PDD and also reduce risk of falling. There is also evidence supporting its use in DLB. Recent evidence suggests that memantine may also be effective, particularly for PDD, although evidence is more conflicting. Memantine may also improve parkinsonism and dyskinesias. Few clinical trials of cognition in PD without dementia exist, but there is preliminary evidence for atomoxetine, memantine, and piribedil. There is a lack of systematic evidence for the treatment of visual hallucinations and depression in PDD and DLB. In addition, there is a need for studies of whether potentially disease-modifying agents can prevent or delay the progression to dementia in PD.

Effect of alternative models for increasing stocking density on the short-term behavior and hygiene of Holstein dairy cows.

The primary objective of this study was to evaluate short-term responses in lying behavior and hygiene of Holstein dairy cows housed at a stocking density of 100 (1 cow per stall and headlock) or 142% imposed by 1) the denial of access to freestalls and headlocks, 2) the denial of access to freestalls, headlocks, and 26.6 m(2) of alley space, or 3) the addition of a rotating group of 14 cows to the resident group of 34 cows. The secondary objective was to determine the bioequivalence of the 3 methods of experimentally increasing stocking density. Cows (n=136) were assigned to 1 of 4 pens in a 4-row freestall barn and treatments were allocated using a 4×4 Latin square with 14-d periods. Lying time (h/d) and number of bouts/d for 12 focal cows per pen were determined using dataloggers recording at 1-min intervals during the final 5 d of each period. Dry matter intake (DMI) was established from the pen mean over the final 4 d of each period. Feeding and rumination activities on focal cows were determined by direct observation at 10-min intervals for 24h on d 11. Hygiene of focal cows was assessed from the difference in the scores after the legs and udder were cleaned on d 2 of each period and those on d 14. Lying time was greater for 100% stocking density (13.0 h/d) than the 142% stocking density treatments (11.8 h/d), which did not differ. Lying bouts (12.3/d) and bout duration (64.8 min/bout) did not differ among treatments. Short-term responses in DMI (24.6 kg/d) did not differ in response to the treatments. The 3 stocking density treatments decreased, or tended to decrease, the time spent feeding compared with 100% (4.4 versus 4.2 h/d). The stocking density treatments decreased the percentage of rumination occurring within a stall (92.3 versus 85.3%). A treatment effect on udder and leg hygiene scores was not evident on d 14 of each period or in the change from d 2 to 14 of each period. With the exception of rumination time (h/d), the 3 methods for experimentally imposing stocking density were bioequivalent for responses in behaviors, DMI, and hygiene. Future stocking density experiments in 4-row barns should simply deny resting and feeding space to simulate overcrowded housing conditions for lactating dairy cows because it is bioequivalent to more complicated, and potentially confounding, research models.