Transthyretin stabilization activity of the catechol-O-methyltransferase inhibitor tolcapone (SOM0226) in hereditary ATTR amyloidosis patients and asymptomatic carriers: proof-of-concept study#

Objective: To assess the transthyretin (TTR) stabilization activity of tolcapone (SOM0226) in patients with hereditary ATTR amyloidosis, asymptomatic carriers and healthy volunteers.

Methods: A phase IIa proof-of-concept trial included two phases separated by a 6-week washout period. Phase A: single 200?mg dose of tolcapone; phase B: three 100?mg doses taken at 4?h intervals. The primary efficacy variable was TTR stabilization.

Results: Seventeen subjects were included (wild type, n?=?6; mutation TTR Val30Met, n?=?11). TTR stabilization was observed in all participants. Two hours after dosing, 82% of participants in phase A and 93% of those in phase B reached a TTR stabilization value of at least 20%. In phase A, there was an increase of 52% in TTR stabilization vs baseline values 2?h after dosing, which decreased to 22.9% at 8?h. In phase B, there was a significant increase of 38.8% in TTR stabilization 2?h after the first 100?mg dose. This difference was maintained after 10?h and decreased after 24?h. No serious adverse events were observed.

Conclusions: The ability of tolcapone for stabilizing TTR supports further development and repositioning of the drug for the treatment of ATTR amyloidosis.

EudraCT trial number: 2014-001586-27

ClinicalTrials.gov Identifier: NCT02191826     

Advance Care Planning Program and the Knowledge and Attitude Concerning Palliative Care

Objectives: The study aimed to evaluate the effects of an advance care planning (ACP) program on knowledge and attitudes concerning palliative care, and decisions regarding DNR orders in the older residents in a long-term care institution.

Methods: A quasi-experimental design was used. Participants were cognitively unimpaired older residents in a long-term care institution in Taiwan. The experimental group (n = 29) received the intervention including an individual interview using an ACP handbook and a group patient education; whereas the control group (n = 28) received the group patient education only.

Results: There were significant positive effects of the ACP program on understanding of DNR and palliative care, willingness to sign a DNR order, and knowledge of and attitude towards palliative care; however, there was no significant effect on willingness to receive palliative care. Six participants signed the DNR order after the intervention compared to none in the control group.

Conclusions: The ACP program can improve knowledge and attitudes towards palliative care in older residents in long-term care institutions.

Clinical Implications: The ACP program could incorporate multiple components, including individual interview using ACP handbook and group patient education, and address knowledge and attitudes towards palliative care.     

Testing hair for fentanyl exposure: a method to inform harm reduction behavior among individuals who use heroin

Background: Deaths from fentanyl exposure continue to increase in the US. Fentanyl test strips are now available to test urine for presence of fentanyl, but additional testing methods are needed to determine past exposure and to determine exposure to specific analogs.

Objectives: To investigate exposure to such analogs through hair testing.

Methods: Forty individuals in inpatient detoxification (7.5% female) reporting past-month heroin use were surveyed and provided a hair sample to be tested at a later date. While results could not be provided to patients, they were asked how they would respond if informed that their hair tested positive for fentanyl. UHPLC-MS/MS was used to test for past exposure to fentanyl, six other novel synthetic opioids, and fentanyl biomarkers/metabolites.

Results: 27.5% reported known fentanyl use in the past year and 67.5% reported suspected exposure. 97.5% (39 of 40) tested positive for fentanyl, 90.0% tested positive for 4-ANPP (a biomarker) and norfentanyl (a metabolite); 82.5% tested positive for acetyl-fentanyl, 47.5% tested positive for furanyl-fentanyl, and 7.5% tested positive for U-47700. Most participants (82.5%) reported they would warn others about fentanyl if they learned their hair tested positive; 75.0% reported they would try to stop using heroin, and 65.0% reported they would ensure that someone nearby has naloxone to reverse a potential overdose.

Conclusions: Hair testing is useful in detecting past exposure to fentanyl, its analogs, and other novel synthetic opioids. Further research is needed to determine whether individuals who use heroin learning about exposure affects drug-taking and treatment-seeking behavior.     

Evaluation of fatigue in inflammatory bowel disease - a useful tool in daily practice

Background: Fatigue is a common symptom reported in inflammatory bowel disease (IBD) patients. It can be severe and modify the self-perception of disease.

Objective: To evaluate the contribution of clinical and demographic factors to the level of fatigue in IBD patients.

Methods: Patients consecutively observed in an outpatient IBD clinic during a 9-month period were studied. Demographic and clinical data were collected. Fatigue was assessed using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F). A FACIT-F score <30 was considered as severe fatigue.

Results: One hundred and five patients were evaluated. Of them, 57.1% had Crohn´s Disease (CD) and 42.9% had Ulcerative Colitis. Also 85.0% and 77.8% were in clinical remission, respectively. The mean FACIT-F score was 39.63?±?9.67. Severe fatigue was observed in 17.1% of patients. Female gender and active CD were significantly associated with a severe level of fatigue (p?=?.05 and p?=?.04). There was no significant correlation between the level of fatigue (severe vs. non-severe) and type of IBD, hemoglobin, C-reactive protein, ferritin levels or previous surgeries. Patients under biological therapy had a significantly higher level of fatigue and a higher rate of previous hospitalizations (p?=?.02).

Conclusions: Fatigue level is a simple and useful tool to evaluate the disease’s impact in patients’ life, and it should, therefore, be included in clinical practice. Biological therapy was associated to higher levels of fatigue. Future studies should evaluate the impact of therapy on the level of fatigue.     

Cognitive Self-Efficacy and Mental Health Ratings after a Memory Skills Group for Older Veterans with PTSD

Objectives: Mental health factors, such as PTSD, can exacerbate typical age-related cognitive changes and lead individuals to have subjective concerns for which few interventions presently exist. This study evaluates self-reported mental health outcomes following a psychoeducational memory skills program designed for veterans over 50 with subjective memory concerns in the context of PTSD. It was hypothesized that outcomes would improve following program participation and that baseline cognitive self-efficacy would moderate improvements in self-reported depression and life satisfaction.

Methods: Veterans (n = 101, age ≥ 51) participated in an 8-week memory skills program and completed baseline and post-program assessment data as part of a quality improvement project.

Results: Life satisfaction and cognitive self-efficacy demonstrated significant improvement following participation in the memory skills program. Cognitive self-efficacy was found to significantly modify change in depressive symptoms.

Conclusions: We found improvement in mental health outcomes following participation in a psychoeducational memory skills program, with differential impact on depressive symptoms for those with low baseline cognitive self-efficacy.

Clinical Implications: Participation in this intervention led to improved life satisfaction and cognitive self-efficacy. Cognitive self-efficacy, in turn, appeared to have implications for improving depressive symptomology and may be a useful target of memory skills education.     

Modelling the role of microbial p-cresol in colorectal genotoxicity

Background: A greater understanding of mechanisms explaining the interactions between diet and the gut microbiota in colorectal cancer is desirable. Genotoxic microbial metabolites present in the colon may be implicated in carcinogenesis and potentially influenced by diet.

Aims: We hypothesised that microbial p-cresol is a colonic genotoxin and set out to model potential exposures in the colon and the effects of these exposures on colonic cells.

Methods: Batch culture fermentations with human faecal inoculate were used to determine the synthesis of p-cresol and other metabolites in response to various substrates. The fermentation supernatants were evaluated for genotoxicity and the independent effects of p-cresol on colonic cells were studied in vitro.

Results: In batch culture fermentation, supplementary protein increased the synthesis of phenols, indoles and p-cresol, whereas supplementary fructoligosaccharide (FOS) increased the synthesis of short chain fatty acids. The p-cresol was the greatest predictor of genotoxicity against colonocytes in the fermentation supernatants. Spiking fermentation supernatants with exogenous p-cresol further increased DNA damage, and independently p-cresol induced DNA damage in a dose-dependent manner against HT29 and Caco-2 cells and influenced cell cycle kinetics.

Conclusions: In the colon p-cresol may reach physiologically significant concentrations which contribute to genotoxic exposures in the intestinal lumen, p-cresol production may be attenuated by substrate, and therefore diet, making it a potential modifiable biomarker of genotoxicity in the colon.     

Gastroesophageal reflux symptoms and microscopic esophagitis in a cohort of consecutive patients affected by atrophic body gastritis: a pilot study

Aim: In patients affected by atrophic body gastritis (ABG) gastro-oesophageal reflux (GER) related symptoms have been reported, despite the presence of hypochlorhydria.

Objective: Objectives of this single-centre study was to assess in ABG the occurrence of GER-related symptoms and their relationship with histopathologic oesophageal findings.

Materials and methods: Fifty-four consecutive patients (20.4%male, 57.6?±?14 years) undergoing to follow-up for ABG, underwent assessment of GER-related symptoms and gastroscopy with multiple gastric and oesophageal biopsies to investigate the presence of microscopic esophagitis (ME).

Results: At least one typical GER symptoms were reported in 24.1% with 9.2% of patients complaining of heartburn and 18.5% regurgitation. One or more atypical GERD symptoms were reported in 44.4% of patients. Two symptomatic ABG patients presented oesophageal lesions at endoscopy (one with erosive esophagitis (LA-C) and one with Barrett’s oesophagus (C2M2)), 49% reported a mild ME and 24.5% a severe ME. No significant differences regarding GERD prevalence were found among patients with or without ME, but cough was the only symptom significantly more frequent in patients with ME (38.95% vs. 7.7%, p?=?.042).

Conclusions: These data showed that GERD is present in a quarter of ABG patients, suggesting that hypochlorhydria not exclude per se arising of oesophageal symptoms. In ABG we found that ME is a frequent finding but its clinical relevance remains to be investigated with further studies.     

Adalimumab in the treatment of chronic pouchitis. A randomized double-blind,placebo-controlled trial

Background: Pouchitis is a complication of ileal pouch-anal anastomosis and occurs in up to 50% of patients 10 years after IPAA with 10% developing refractory pouchitis.

Objective: To evaluate the effect of a TNF-α inhibitor (Adalimumab) in the treatment of refractory pouchitis.

Materials and methods: A multicenter, randomized double-blind, placebo-controlled trial includes patients with refractory pouchitis for more than 4 weeks despite antibiotic treatment. Patients were randomized to Adalimumab or placebo for 12 weeks. Primary outcome was reduction in clinical pouchitis disease activity index (PDAI) of ≥2 at any time. Secondary endpoints were remission of pouchitis, endoscopic and histologic effect and quality of life.

Results: Thirteen patients were included; six patients received active treatment and seven patients received placebo. Nine patients (5/4, Adalimumab/placebo) completed the 12-week program. Reduction in clinical PDAI ≥ 2 was achieved in three patients in each group (50%/43%, Adalimumab/placebo, p?>?.5). Total PDAI improved in six patients treated with Adalimumab and two patients on placebo (100%/29%, p?=?.13). There were no differences in secondary endpoints between the groups.

Conclusions: In this randomized controlled trial of treatment with Adalimumab in patients with refractory pouchitis, we were not able to identify any clinical benefit in the primary or secondary endpoints.     

Telephone-Delivered Cognitive Behavioural Therapy for Treating Symptoms of Anxiety and Depression in Parkinson’s Disease: A Pilot Trial

Objectives: To determine the feasibility, acceptability and initial efficacy of telephone-delivered cognitive behavioral therapy (CBT) for the treatment of anxiety and depressive symptoms in people with Parkinson’s disease.

Methods: A small randomized controlled trial compared telephone-based CBT to waitlist control. Eleven participants aged >50 years with Parkinson’s disease and anxiety and/or depressive symptoms above recommended clinical cut-offs, were randomized to one of two conditions. Participants completed self-report measures of symptom severity and quality of life. Their carers were invited to participate and completed self-reported measures of symptoms and carer burden. At the end of the 10-week intervention period, participants and carers were reassessed on baseline measures, and again one month later.

Results: The CBT program was associated with significantly reduced depressive symptoms (Cohen’s d = .90) at post-treatment with gains maintained at one-month follow-up. Anxiety symptom decreases (Cohen’s d = 0.36) were not statistically different. Waitlist was associated with significantly worsened anxiety. Carer symptoms also reduced with CBT. No changes on quality of life were found. Good acceptability and feedback was received.

Conclusions: Telephone-based CBT reduced symptoms of depression in participants with Parkinson’s disease but not anxiety.

Clinical Implications: Telephone-based CBT is a promising treatment option.     

Reference intervals of aortic pulse wave velocity assessed with an oscillometric device in healthy children and adolescents from Argentina

Age-related reference intervals (RIs) of aortic pulse wave velocity (Ao-PWV) obtained from a large healthy population are lacking in South America. The aims of this study were to determine Ao-PWV RIs in a cohort of healthy children and adolescents from Argentina and to generate year-to-year percentile curves.

Ao-PWV was measured in 1000 healthy subjects non-exposed to traditional cardiovascular risk factors (Age: 10–22 y. o., 56% males). First, we evaluated if RIs for males and females were necessaries (correlation and covariate analysis). Second, mean (M) and standard deviation (SD) age-related equations were obtained for cf-PWV, using parametric regression methods based on fractional polynomials. Third, age-specific (year to year) percentiles curves (for all, males and females children and adolescents) were generated using the standard normal distribution. They were, age-specific 1st, 2.5th, 5th, 10th, 25th, 50th, 75th, 90th, 95th, 97.5th and 99th percentile curves and values.

After covariate analysis (i.e., adjusting by age, jugulum-symphysis distance, body weight and height), specific RIs for males and females of children and adolescents were evidenced as necessaries. The equations were

For all subjects:

Ao-PWV_Mean = 4.98 + 12.86x10^?5 Age³.

Ao-PWV_SD = 0.47 + 21.00x10^?6Age³.

For girls:

Ao-PWV_Mean = 5.07 + 10.23x10^?5Age³.

Ao-PWV_SD = 0.50 + 10.00x10^?6Age³.

For boys:

Ao-PWV_Mean = 4.87 + 15.81x10^?5Age³.

Ao-PWV_SD = 0.46 + 22.34x10^?6Age³.

Our study provides the largest database to-date concerning Ao-PWV in healthy children and adolescents in Argentina. Age-related equations (M and SD values) for Ao-PWV are reported by the first time. Specific RIs and percentiles of Ao-PWV are now available according to age and sex for an Argentinian population.     

Memory Performance of People with Different Dementia Severity for Different Semantic Hierarchies

Background: Memory disorder is a significant symptom during early-stage Alzheimer’s disease (AD). Changes in semantic memory are frequently seen in terms of forgetting names, loss of word meanings, and difficulties in linguistic expression. Significant semantic degeneration is not a normal phenomenon in elderly persons, and it may be an important sign in the early stages of progression of AD.

Methods: Thirty-four participants aged between 60 and 86 years were recruited for an experiment with a 3 × 4 × 2 factorial design that was conducted to explore the differences in semantic memory performance among controls with normal cognitive performance (NC), individuals classified as mildly cognitively impaired (MCI), and individuals with AD.

Results: The performance of participants diagnosed with mild AD was poorest for the attribute category, and there was no difference in response to different word frequencies. Although those diagnosed with MCI performed similarly to healthy elderly participants in terms of semantic memory, their performance profiles for different semantic hierarchies were similar to those of participants with AD.

Conclusion: Semantic memory had degraded among participants with AD and MCI, and the rate of semantic degeneration was different in different semantic hierarchies.     

Positive Aging: The Impact of a Community Wellbeing and Resilience Program

Objectives: To test the effect of a community wellbeing intervention, delivered by community partners, on the wellbeing, resilience, optimism, and social connection of older adults in the general population (Study 1) and older adult carers (Study 2), a population at risk for low wellbeing.

Methods: Participants self-selected to take part in an 8-week multi-component wellbeing and resilience program consisting of weekly training sessions, and optional mentoring/peer support. Program participants and a natural control group were compared, post-intervention, on all outcomes of interest.

Results: Intervention participants (Study 1) reported significantly lower scores of social isolation, but no significant difference in wellbeing, optimism, or resilience. Intervention participants (Study 2) showed significantly higher scores on all measured outcomes except social isolation.

Conclusion: These studies point towards the potential benefits of wellbeing interventions for older adult from the general population and older adult carers, when delivered by community partners.

Clinical implications: Early interventions promoting mental health may contribute to reducing the burden of mental health conditions on individuals and the health care system. Studies with more rigorous designs and extended follow-up measurements are required to consolidate these positive initial findings.     

Facilitating Family Life Review during a Relocation to Assisted Living: Exploring Contextual Impact on Family Adjustment

Objectives: The purpose of this study was to explore how contextual aspects of participants’ lives before and throughout relocation to assisted living (ALF) informed family experience of family life review (FLR).

Method: Fourteen families participated in a single FLR session within 6 months of the older adults’ relocation. Semi-structured interviews, conducted one-month following the FLR session, were analyzed using the constant comparative method. Demographic and relational variables provided context for assessing how individual and family dynamics influenced the family relocation process.

Results: Techniques were used during the three phases of FLR (introduction, validation, consolidation) to encourage openness and mutual dialogue between family members. Health-related limitations challenged older adults’ understanding and openness during the FLR. Mental health concerns linked to older adults’ outlook on life, comfort in conversation during the FLR, and reflection of lifelong social ties. Family involvement and dynamics influenced how families communicated about their mutual narrative and the relocation transition.

Conclusion: FLR is an adaptable intervention to assist older adults and their family during a transition to ALF. Although contextual challenges impacted how families experienced the FLR, they enjoyed FLR as a unifying event that promoted mutual understanding.

Clinical Implications: The use of FLR facilitates enhanced understanding and communication during relocation. Older adults’ health status as well as family dynamics need to be assessed prior to organizing a FLR to accommodate each families’ unique needs.     

Social intolerance,risky sexual behaviors and their association with HIV knowledge among Ugandan adults: results from a national survey

Understanding the link between HIV knowledge, risky sexual behaviors, and social intolerance such as stigma and discrimination is important for HIV prevention and treatment program planning. We investigated whether intolerant attitudes and practices among Ugandan adults were associated with HIV-transmission knowledge.

We analyzed data from a nationally representative population-based household survey, the 2011 Uganda AIDS Indicator Survey. A total of 15,526 participants who responded to questions on HIV knowledge, social intolerance and risky sexual behavior were included in this analysis.

Results show that 34.8% of respondents reported having fear of casual contact with people living with HIV (PLWA), 21% blame PLWAs for their disease, 62% would not want HIV infection in their family disclosed, while 25% reported engaging in risky sexual behaviors. After adjusting for age, sex, residence, and level of education, people with low HIV-transmission knowledge had almost three-fold higher odds of fear of casual contact with a PLWA (aOR?=?2.70, 95%CI?=?2.33–3.13), and had 30% higher odds of HIV-related stigmatizing attitudes (aOR?=?1.29, 95%CI?=?1.07–1.54). Further, they had 47% higher odds of having sex under the influence of alcohol (aOR?=?1.47, 95%CI?=?1.25–1.73) and 40% higher odds of having unprotected sex with any of their last three sex partners (aOR?=?1.39, 95%CI?=?1.06–1.89).

Our findings show that intolerant attitudes such as stigma still persist, particularly among people with low HIV-transmission knowledge. Improving knowledge about HIV/AIDS can foster positive attitudes and building safe practices among populations, and is critical for improving prevention and treatment programs.     

Factors related to paradoxical reactions during propofol-induced sedated endoscopy

Objective: The factors related to paradoxical excitement during propofol-induced sedation remain unclear. We aimed to investigate this issue during sedated upper endoscopy.

Material and methods: Among the health examinees scheduled for sedated upper endoscopy from June 2017 to December 2017, 421 participated in the study. Endoscopists were blinded to the information about the examinees and evaluated the development of paradoxical reactions. Propofol was exclusively used as the sedative agent via intermittent bolus injection. A multiple logistic regression analysis was performed to investigate the factors associated with paradoxical reactions.

Results: The incidence of paradoxical reactions was 16.1%. Anxiety (adjusted odds ratio: 2.76; 95% confidence interval: 1.46???5.27; p?=?.002) and age (odds ratio: 0.92; 95% confidence interval: 0.89???0.96; p?<?.001) were significantly associated with paradoxical reactions. Of the nine items of the anxiety questionnaire, four had independent and significant associations with paradoxical reactions (i.e., excess worry, sleeping problems, somatic symptoms, and health concerns; odds ratios: 2.38, 2.71, 2.27 and 2.39, respectively).

Conclusion: Propofol-induced paradoxical reactions tend to occur when an individual has anxiety and is of a young age. Further large population-based studies should be performed to confirm this phenomenon.     

Neuronal correlates of delay discounting in healthy subjects and its implication for addiction: an ALE meta-analysis study

Background: Delay discounting (DD) describes the phenomenon of devaluing future rewards in favor of immediate rewards. Increased DD is a key behavioral marker of addiction, and has been suggested as a target for interventions to alleviate addiction symptoms (e.g., preference for immediate drug use over larger-and-later rewards, and relapses) in patients with substance use disorders (SUD).

Objectives: Performed a meta-analysis on neuroimaging results of DD regarding specific contrasts in healthy participants. Reviewed the results of existing patient studies in light of the meta-analyses results.

Methods: We conducted activation likelihood estimation meta-analyses on DD neuroimaging studies (25 studies, n = 583; 354 males and 229 females) regarding six analytic strategies.

Results: The meta-analyses revealed various subdivisions of the cortical-basal ganglia circuits that are associated with different aspects of DD in healthy subjects. By comparing the meta-analyses results and patients’ studies regarding each contrast, we highlighted three brain regions that may underlie excessive DD in patients. Decreased left inferior frontal gyrus (IFG) activity was related to less preference for delayed choices; reduced ventral striatum (VS) activity was associated with impaired valuation processes; and declined anterior cingulate cortex (ACC)/medial prefrontal cortex (mPFC) activity was associated with alterations in processing difficult choices.

Conclusions: We propose that neuromodulation (e.g. deep brain simulation) or behavioral interventions (e.g. episodic future imagination) targeting these key brain regions (IFG, VS, ACC/mPFC) may be effective for improving DD function in patients with SUD, enhancing valuations of future rewards and helping to resist the temptation of immediate drug use.