Association of cognition with functional trajectories in patients admitted to geriatric wards: A retrospective observational study.

AIM: Impaired cognition is common among older patients admitted to acute hospitals, but its association with functional trajectories has not been well studied. METHODS: A retrospective observational study was carried out in an English tertiary university hospital. We analyzed all first episodes of county residents aged ≥75 years admitted to the Department of Medicine for the Elderly wards between December 2014 and May 2015. A history of dementia or a cognitive concern in the absence of a known diagnosis of dementia were recorded on admission. A cognitive concern included possible undiagnosed dementia or delirium. Function was retrospectively measured with the modified Rankin Scale at preadmission baseline, admission and discharge. RESULTS: There were 663 first hospital episodes over the period, of which 590 patients survived. Among the latter, 244 had no cognitive impairment, 134 a diagnosis of dementia, 66 a cognitive concern in the absence of a known dementia and 146 had missing cognitive data. When frailty, acuity, age and comorbidity were controlled for, people with known dementia had a similar functional recovery compared with those with no cognitive impairment. People with a cognitive concern, but no known dementia, had lesser functional recovery and greater disability at discharge than those with no cognitive impairment (mean discharge modified Rankin Scale 3.4 compared with 3.1, P = 0.011). CONCLUSIONS: Dementia per se might not be a marker of poor rehabilitation potential. Older people with acute cognitive concerns might be more vulnerable to poor functional recovery. Our cognitive variables are not gold standard, and further research is required to clarify this relationship. Geriatr Gerontol Int 2017; 17: 1438-1443.This is the author accepted manuscript. The final version is available from Wiley via https://doi.org/10.1111/ggi.1288

Clinical frailty and functional trajectories in hospitalized older adults: A retrospective observational study.

AIM: Frailty predicts inpatient mortality and length of stay, but its link to functional trajectories is under-researched. Addenbrooke's Hospital, Cambridge, UK, collects the Clinical Frailty Scale (CFS) within 72 h of admission for those aged ≥75 years. We studied whether the CFS links to functional trajectories in hospitalized older adults. METHODS: This was a retrospective observational study in an English university hospital. We analyzed all first episodes of county residents aged ≥75 years admitted to the Department of Medicine for the Elderly wards between December 2014 and May 2015. Data were extracted from the hospital's information systems. Patients were classified as non-frail (CFS 1-4), moderately frail (CFS 5-6) and severely frail (CFS 7-8). Function was retrospectively measured with the modified Rankin Scale (mRS) at preadmission, admission and discharge. RESULTS: Of 539 eligible patients, 46 died during admission (mortality rates: 2% in CFS 1-4, 5% in CFS 5-6, 19% in CFS 7-8). Among the 493 survivors, 121 were non-frail, 235 moderately and 137 severely frail. The mean mRS of the non-frail was 1.8 (95% CI 1.7-2.0) at baseline, 3.3 (95% CI 3.1-3.5) on admission and 2.2 (95% CI 2.0-2.3) on discharge (mean length of stay 9 days). The moderately frail had a mean mRS of 2.9 (95% CI 2.8-3.0) at baseline, 4.0 (95% CI 3.8-4.1) on admission and 3.2 (95% CI 3.1-3.3) on discharge (mean length of stay 15 days). The severely frail had mean mRS of 3.5 (95% CI 3.3-3.6) at baseline, 4.3 (95% CI 4.1-4.4) on admission and 3.7 (95% CI 3.6-3.9) on discharge, respectively (mean length of stay 17 days). CONCLUSIONS: In older inpatients, frailty might be linked to lower and slower functional recovery. Prospective work is required to confirm these trajectories and understand how to influence them. Geriatr Gerontol Int 2017; 17: 1063-1068.Funding was not required for this study.This is the author accepted manuscript. The final version is available from Wiley via https://doi.org/ 10.1111/ggi.1282

Prevalence of mental health disorders in inflammatory bowel disease: an Australian outpatient cohort

BACKGROUND: This study aimed to characterize prevalence of anxiety and depressive conditions and uptake of mental health services in an Australian inflammatory bowel disease (IBD) outpatient setting. METHODS: Eighty-one IBD patients (39 males, mean age 35 years) attending a tertiary hospital IBD outpatient clinic participated in this study. Disease severity was evaluated according to the Manitoba Index. Diagnosis of an anxiety or depressive condition was based upon the Mini-International Neuropsychiatric Interview and the Hospital Anxiety and Depression Scale. RESULTS: Based on Hospital Anxiety and Depression Scale subscale scores >8 and meeting Mini-International Neuropsychiatric Interview criteria, 16 (19.8%) participants had at least one anxiety condition, while nine (11.1%) had a depressive disorder present. Active IBD status was associated with higher prevalence rates across all anxiety and depressive conditions. Generalized anxiety was the most common (12 participants, 14.8%) anxiety condition, and major depressive disorder (recurrent) was the most common depressive condition reported (five participants, 6.2%). Seventeen participants (21%) reported currently seeking help for mental health issues while 12.4% were identified has having at least one psychological condition but not seeking treatment. CONCLUSION: We conclude that rates of anxiety and depression are high in this cohort, and that IBD-focused psychological services should be a key component of any holistic IBD service, especially for those identified as having active IBD

Global meta‐analysis of over 50 years of multidisciplinary and international collaborations on transmissible cancers

International audienceAlthough transmissible cancers have, so far, only been documented in three independent animal groups, they not only impact animals that have high economic, environmental and social significance, but they are also one of the most virulent parasitic life forms. Currently known transmissible cancers traverse terrestrial and marine environments, and are predicted to be more widely distributed across animal groups; thus, the implementation of effective collaborative scientific networks is important for combating existing and emerging forms. Here, we quantify how collaborative effort on the three known transmissible cancers has advanced through the formation of collaborative networks among institutions and disciplines. These three cancers occur in bivalves (invertebrates—disseminated neoplasia; DN), Tasmanian devils (vertebrate—marsupial; devil facial tumour disease; DFTD) and dogs (vertebrate—eutherian mammal; canine transmissible venereal tumour; CTVT). Research on CTVT and DN has been conducted since 1876 and 1969, respectively, whereas systematic research on DFTD only started in 2006. Yet, collaborative effort on all three diseases is global, encompassing six major Scopus subject areas. Collaborations steadily increased between 1963 and 2006 for CTVT and DN, with similar acceleration for all three cancers since 2006. Network analyses demonstrated that scientists are organizing themselves into efficient collaborative networks; however, these networks appear to be far stronger for DFTD and DN, possibly due to the recent detection of new strains adding impetus to research and associated publications (enhancing citation trajectories). In particular, global and multidisciplinary collaborations formed almost immediately after DFTD research was initiated, leading to similar research effort and relatively greater research outputs compared to the other two diseases. Therefore, in the event of outbreaks of new lineages of existing transmissible cancers, or the discovery of new transmissible cancers in the future, the rapid formation of international collaborations spanning relevant disciplines is vital for the efficient management of these diseases

Removing the Threat of Diclofenac to Critically Endangered Asian Vultures

Veterinary use of the nonsteroidal anti-inflammatory (NSAID) drug diclofenac in South Asia has resulted in the collapse of populations of three vulture species of the genusGyps to the most severe category of global extinction risk. Vultures are exposed to diclofenac when scavenging on livestock treated with the drug shortly before death. Diclofenac causes kidney damage, increased serum uric acid concentrations, visceral gout, and death. Concern about this issue led the Indian Government to announce its intention to ban the veterinary use of diclofenac by September 2005. Implementation of a ban is still in progress late in 2005, and to facilitate this we sought potential alternative NSAIDs by obtaining information from captive bird collections worldwide. We found that the NSAID meloxicam had been administered to 35 captiveGyps vultures with no apparent ill effects. We then undertook a phased programme of safety testing of meloxicam on the African white-backed vultureGyps africanus, which we had previously established to be as susceptible to diclofenac poisoning as the endangered AsianGyps vultures. We estimated the likely maximum level of exposure (MLE) of wild vultures and dosed birds by gavage (oral administration) with increasing quantities of the drug until the likely MLE was exceeded in a sample of 40G. africanus. Subsequently, sixG. africanus were fed tissues from cattle which had been treated with a higher than standard veterinary course of meloxicam prior to death. In the final phase, ten Asian vultures of two of the endangered species(Gyps bengalensis,Gyps indicus) were dosed with meloxicam by gavage; five of them at more than the likely MLE dosage. All meloxicam-treated birds survived all treatments, and none suffered any obvious clinical effects. Serum uric acid concentrations remained within the normal limits throughout, and were significantly lower than those from birds treated with diclofenac in other studies. We conclude that meloxicam is of low toxicity toGyps vultures and that its use in place of diclofenac would reduce vulture mortality substantially in the Indian subcontinent. Meloxicam is already available for veterinary use in India

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Thromboxane biosynthesis in cancer patients and its inhibition by aspirin: a sub-study of the Add-Aspirin trial

BACKGROUND: Pre-clinical models demonstrate that platelet activation is involved in the spread of malignancy. Ongoing clinical trials are assessing whether aspirin, which inhibits platelet activation, can prevent or delay metastases. METHODS: Urinary 11-dehydro-thromboxane B2 (U-TXM), a biomarker of in vivo platelet activation, was measured after radical cancer therapy and correlated with patient demographics, tumour type, recent treatment, and aspirin use (100 mg, 300 mg or placebo daily) using multivariable linear regression models with log-transformed values. RESULTS: In total, 716 patients (breast 260, colorectal 192, gastro-oesophageal 53, prostate 211) median age 61 years, 50% male were studied. Baseline median U-TXM were breast 782; colorectal 1060; gastro-oesophageal 1675 and prostate 826 pg/mg creatinine; higher than healthy individuals (~500 pg/mg creatinine). Higher levels were associated with raised body mass index, inflammatory markers, and in the colorectal and gastro-oesophageal participants compared to breast participants (P < 0.001) independent of other baseline characteristics. Aspirin 100 mg daily decreased U-TXM similarly across all tumour types (median reductions: 77-82%). Aspirin 300 mg daily provided no additional suppression of U-TXM compared with 100 mg. CONCLUSIONS: Persistently increased thromboxane biosynthesis was detected after radical cancer therapy, particularly in colorectal and gastro-oesophageal patients. Thromboxane biosynthesis should be explored further as a biomarker of active malignancy and may identify patients likely to benefit from aspirin

HIV integration and the establishment of latency in CCL19-treated resting CD4(+) T cells require activation of NF-κB

BACKGROUND: Eradication of HIV cannot be achieved with combination antiretroviral therapy (cART) because of the persistence of long-lived latently infected resting memory CD4(+) T cells. We previously reported that HIV latency could be established in resting CD4(+) T cells in the presence of the chemokine CCL19. To define how CCL19 facilitated the establishment of latent HIV infection, the role of chemokine receptor signalling was explored. RESULTS: In resting CD4(+) T cells, CCL19 induced phosphorylation of RAC-alpha serine/threonine-protein kinase (Akt), nuclear factor kappa B (NF-&kappa;B), extracellular-signal-regulated kinase (ERK) and p38. Inhibition of the phosphoinositol-3-kinase (PI3K) and Ras/Raf/Mitogen-activated protein kinase/ERK kinase (MEK)/ERK signalling pathways inhibited HIV integration, without significant reduction in HIV nuclear entry (measured by Alu-LTR and 2-LTR circle qPCR respectively). Inhibiting activation of MEK1/ERK1/2, c-Jun N-terminal kinase (JNK), activating protein-1 (AP-1) and NF-&kappa;B, but not p38, also inhibited HIV integration. We also show that HIV integrases interact with Pin1 in CCL19-treated CD4(+) T cells and inhibition of JNK markedly reduced this interaction, suggesting that CCL19 treatment provided sufficient signals to protect HIV integrase from degradation via the proteasome pathway. Infection of CCL19-treated resting CD4(+) T cells with mutant strains of HIV, lacking NF-&kappa;B binding sites in the HIV long terminal repeat (LTR) compared to infection with wild type virus, led to a significant reduction in integration by up to 40-fold (range 1-115.4, p&nbsp;=&nbsp;0.03). This was in contrast to only a modest reduction of 5-fold (range 1.7-11, p&nbsp;&gt;&nbsp;0.05) in fully activated CD4(+) T cells infected with the same mutants. Finally, we demonstrated significant differences in integration sites following HIV infection of unactivated, CCL19-treated, and fully activated CD4(+) T cells. CONCLUSIONS: HIV integration in CCL19-treated resting CD4(+) T cells depends on NF-&kappa;B signalling and increases the stability of HIV integrase, which allow subsequent integration and establishment of latency. These findings have implications for strategies needed to prevent the establishment, and potentially reverse, latent infection

Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis (New EPOC): long-term results of a multicentre, randomised, controlled, phase 3 trial.

BACKGROUND: The interim analysis of the multicentre New EPOC trial in patients with resectable colorectal liver metastasis showed a significant reduction in progression-free survival in patients allocated to cetuximab plus chemotherapy compared with those given chemotherapy alone. The focus of the present analysis was to assess the effect on overall survival. METHODS: New EPOC was a multicentre, open-label, randomised, controlled, phase 3 trial. Adult patients (aged ≥18 years) with KRAS wild-type (codons 12, 13, and 61) resectable or suboptimally resectable colorectal liver metastases and a WHO performance status of 0-2 were randomly assigned (1:1) to receive chemotherapy with or without cetuximab before and after liver resection. Randomisation was done centrally with minimisation factors of surgical centre, poor prognosis cancer, and previous adjuvant treatment with oxaliplatin. Chemotherapy consisted of oxaliplatin 85 mg/m2 administered intravenously over 2 h, l-folinic acid (175 mg flat dose administered intravenously over 2 h) or d,l-folinic acid (350 mg flat dose administered intravenously over 2 h), and fluorouracil bolus 400 mg/m2 administered intravenously over 5 min, followed by a 46 h infusion of fluorouracil 2400 mg/m2 repeated every 2 weeks (regimen one), or oxaliplatin 130 mg/m2 administered intravenously over 2 h and oral capecitabine 1000 mg/m2 twice daily on days 1-14 repeated every 3 weeks (regimen two). Patients who had received adjuvant oxaliplatin could receive irinotecan 180 mg/m2 intravenously over 30 min with fluorouracil instead of oxaliplatin (regimen three). Cetuximab was given intravenously, 500 mg/m2 every 2 weeks with regimen one and three or a loading dose of 400 mg/m2 followed by a weekly infusion of 250 mg/m2 with regimen two. The primary endpoint of progression-free survival was published previously. Secondary endpoints were overall survival, preoperative response, pathological resection status, and safety. Trial recruitment was halted prematurely on the advice of the Trial Steering Committee on Nov 1, 2012. All analyses (except safety) were done on the intention-to-treat population. Safety analyses included all randomly assigned patients. This trial is registered with ISRCTN, number 22944367. FINDINGS: Between Feb 26, 2007, and Oct 12, 2012, 257 eligible patients were randomly assigned to chemotherapy with cetuximab (n=129) or without cetuximab (n=128). This analysis was carried out 5 years after the last patient was recruited, as defined in the protocol, at a median follow-up of 66·7 months (IQR 58·0-77·5). Median progression-free survival was 22·2 months (95% CI 18·3-26·8) in the chemotherapy alone group and 15·5 months (13·8-19·0) in the chemotherapy plus cetuximab group (hazard ratio [HR] 1·17, 95% CI 0·87-1·56; p=0·304). Median overall survival was 81·0 months (59·6 to not reached) in the chemotherapy alone group and 55·4 months (43·5-71·5) in the chemotherapy plus cetuximab group (HR 1·45, 1·02-2·05; p=0·036). There was no significant difference in the secondary outcomes of preoperative response or pathological resection status between groups. Five deaths might have been treatment-related (one in the chemotherapy alone group and four in the chemotherapy plus cetuximab group). The most common grade 3-4 adverse events reported were: neutrophil count decreased (26 [19%] of 134 in the chemotherapy alone group vs 21 [15%] of 137 in the chemotherapy plus cetuximab group), diarrhoea (13 [10%] vs 14 [10%]), skin rash (one [1%] vs 22 [16%]), thromboembolic events (ten [7%] vs 11 [8%]), lethargy (ten [7%] vs nine [7%]), oral mucositis (three [2%] vs 14 [10%]), vomiting (seven [5%] vs seven [5%]), peripheral neuropathy (eight [6%] vs five [4%]), and pain (six [4%] vs six [4%]). INTERPRETATION: Although the addition of cetuximab to chemotherapy improves the overall survival in some studies in patients with advanced, inoperable metastatic disease, its use in the perioperative setting in patients with operable disease confers a significant disadvantage in terms of overall survival. Cetuximab should not be used in this setting. FUNDING: Cancer Research UK