Stakeholder collaboration and heritage management

This article examines a collaborative approach to the relationship between heritage management and tourism development in Luang Prabang, Laos. The purpose is to examine stakeholder collaboration and management roles, heritage tourism development, as well as the interdependence of the heritage conservation and tourism relationship. The research examines a UNESCO/Norwegian government project, which aiming to promote collaboration between heritage conservation and tourism through stakeholder involvement. Five aspects are explored: channels of communication between the heritage and the tourism groups, generating income for heritage conservation and management, involving the local community in decisionmaking, involving the local community in tourism activities, and an assessment of the extent and success of stakeholder collaboration

Estimating the number of contributors to two-, three-, and four-person mixtures containing DNA in high template and low template amounts

Aim To develop guidelines to estimate the number of contributors to two-, three-, and four-person mixtures containing either high template DNA (HT-DNA) or low template DNA (LT-DNA) amounts. Methods Seven hundred and twenty-eight purposeful two-, three-, and four-person mixtures composed of 85 individuals of various ethnicities with template amounts ranging from 10 to 500 pg were examined. The number of alleles labeled at each locus and the number of labeled different and repeating alleles at each locus as well over all loci for 2 HT-DNA or 3 LT-DNA replicates were determined. Guidelines based on these data were then evaluated with 117 mixtures generated from items handled by known individuals. Results The number of different alleles over all loci and replicates was used to initially categorize mixtures. Ranges were established based on the averages plus and minus 2 standard deviations, and to encompass all observations, the maximum and the minimum values. To differentiate samples that could be classified in more than one grouping, the number of loci with 4 or more repeating or different alleles, which were specific to three- and four-person mixtures, were verified. Misclassified samples showed an extraordinary amount of allele sharing or stutter. Conclusions These guidelines proved to be useful tools to distinguish low template and high template two-, three-, and four-person mixtures. Due to the inherent higher probability of allele sharing, four-person mixtures were more challenging. Because of allelic drop-out, this was also the case for samples with very low amounts of template DNA or extreme mixture ratios

If-conditionals and Modality: Frequency patterns and theoretical explanations

It has often been claimed that conditionals have a special relation to modality. This study tests this claim empirically by examining the frequency of modal marking in a number of conditional and non-conditional structures using a corpus-based approach. It then seeks to provide explanations for the emerging frequency patterns in light of the tenets of two linguistic theories: Lexical Grammar and Construction Grammar. This juxtaposition was motivated by the substantial overlap in their tenets: both take into account meaning (semantic and pragmatic), as well as lexical and grammatical factors.</p

Biochemical and Structural Characterization of Selective Allosteric Inhibitors of the Plasmodium falciparum Drug Target, Prolyl-tRNA-synthetase

Plasmodium falciparum (<i>Pf</i>) prolyl-tRNA synthetase (ProRS) is one of the few chemical-genetically validated drug targets for malaria, yet highly selective inhibitors have not been described. In this paper, approximately 40,000 compounds were screened to identify compounds that selectively inhibit <i>Pf</i>ProRS enzyme activity versus Homo sapiens (<i>Hs</i>) ProRS. X-ray crystallography structures were solved for apo, as well as substrate- and inhibitor-bound forms of <i>Pf</i>ProRS. We identified two new inhibitors of <i>Pf</i>ProRS that bind outside the active site. These two allosteric inhibitors showed >100 times specificity for <i>Pf</i>ProRS compared to <i>Hs</i>ProRS, demonstrating this class of compounds could overcome the toxicity related to <i>Hs</i>ProRS inhibition by halofuginone and its analogues. Initial medicinal chemistry was performed on one of the two compounds, guided by the cocrystallography of the compound with <i>Pf</i>ProRS, and the results can instruct future medicinal chemistry work to optimize these promising new leads for drug development against malaria

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]

Effect of hearing intervention on communicative function: A secondary analysis of the ACHIEVE randomized controlled trial

BACKGROUND: The Aging and Cognitive Health Evaluation in Elders (ACHIEVE) Study was designed to determine the effects of a best-practice hearing intervention on cognitive decline among community-dwelling older adults. Here, we conducted a secondary analysis of the ACHIEVE Study to investigate the effect of hearing intervention on self-reported communicative function. METHODS: The ACHIEVE Study is a parallel-group, unmasked, randomized controlled trial of adults aged 70-84 years with untreated mild-to-moderate hearing loss and without substantial cognitive impairment. Participants were randomly assigned (1:1) to a hearing intervention (audiological counseling and provision of hearing aids) or a control intervention of health education (individual sessions with a health educator covering topics on chronic disease prevention) and followed semiannually for 3 years. Self-reported communicative function was measured with the Hearing Handicap Inventory-Elderly Screening version (HHIE-S, range 0-40, higher scores indicate greater impairment). Effect of hearing intervention versus control on HHIE-S was analyzed through an intention-to-treat model controlling for known covariates. RESULTS: HHIE-S improved after 6-months with hearing intervention compared to control, and continued to be better through 3-year follow-up. We estimated a difference of -8.9 (95% CI: -10.4, -7.5) points between intervention and control groups in change in HHIE-S score from baseline to 6 months, -9.3 (95% CI: -10.8, -7.9) to Year 1, -8.4 (95% CI: -9.8, -6.9) to Year 2, and - 9.5 (95% CI: -11.0, -8.0) to Year 3. Other prespecified sensitivity analyses that varied analytical parameters did not change the observed results. CONCLUSIONS: Hearing intervention improved self-reported communicative function compared to a control intervention within 6 months and with effects sustained through 3 years. These findings suggest that clinical recommendations for older adults with hearing loss should encourage hearing intervention that could benefit communicative function and potentially have positive downstream effects on other aspects of health

Addition of four doses of rituximab to standard induction chemotherapy in adult patients with precursor B-cell acute lymphoblastic leukaemia (UKALL14): a phase 3, multicentre, randomised controlled trial

BACKGROUND: Treatment for adults with acute lymphoblastic leukaemia requires improvement. UKALL14 was a UK National Cancer Research Institute Adult ALL group study that aimed to determine the benefit of adding the anti-CD20 monoclonal antibody, rituximab, to the therapy of adults with de novo B-precursor acute lymphoblastic leukaemia. METHODS: This was an investigator-initiated, phase 3, randomised controlled trial done in all UK National Health Service Centres treating patients with acute lymphoblastic leukaemia (65 centres). Patients were aged 25-65 years with de-novo BCR-ABL1-negative acute lymphoblastic leukaemia. Patients with de-novo BCR-ABL1-positive acute lymphoblastic leukaemia were eligible if they were aged 19-65 years. Participants were randomly assigned (1:1) to standard-of-care induction therapy or standard-of-care induction therapy plus four doses of intravenous rituximab (375 mg/m2 on days 3, 10, 17, and 24). Randomisation used minimisation and was stratified by sex, age, and white blood cell count. No masking was used for patients, clinicians, or staff (including the trial statistician), although the central laboratory analysing minimal residual disease and CD20 was masked to treatment allocation. The primary endpoint was event-free survival in the intention-to-treat population. Safety was assessed in all participants who started trial treatment. This study is registered with ClincialTrials.gov, NCT01085617. FINDINGS: Between April 19, 2012, and July 10, 2017, 586 patients were randomly assigned to standard of care (n=292) or standard of care plus rituximab (n=294). Nine patients were excluded from the final analysis due to misdiagnosis (standard of care n=4, standard of care plus rituximab n=5). In the standard-of-care group, median age was 45 years (IQR 22-65), 159 (55%) of 292 participants were male, 128 (44%) were female, one (<1%) was intersex, and 143 (59%) of 244 participants had high-risk cytogenetics. In the standard-of-care plus rituximab group, median age was 46 years (IQR 23-65), 159 (55%) of 294 participants were male, 130 (45%) were female, and 140 (60%) of 235 participants had high-risk cytogenetics. After a median follow-up of 53·7 months (IQR 40·3-70·4), 3-year event-free survival was 43·7% (95% CI 37·8-49·5) for standard of care versus 51·4% (45·4-57·1) for standard of care plus rituximab (hazard ratio [HR] 0·85 [95% CI 0·69-1·06]; p=0·14). The most common adverse events were infections and cytopenias, with no difference between the groups in the rates of adverse events. There were 11 (4%) fatal (grade 5) events in induction phases 1 and 2 in the standard-of-care group and 13 (5%) events in the standard-of-care plus rituximab group). 3-year non-relapse mortality was 23·7% (95% CI 19·0-29·4) in the standard-of-care group versus 20·6% (16·2-25·9) in the standard-of-care plus rituximab group (HR 0·88 [95% CI 0·62-1·26]; p=0·49). INTERPRETATION: Standard of care plus four doses of rituximab did not significantly improve event-free survival over standard of care. Rituximab is beneficial in acute lymphoblastic leukaemia but four doses during induction is likely to be insufficient. FUNDING: Cancer Research UK and Blood Cancer UK

Hearing Impairment and Physical Activity and Physical Functioning in Older Adults: Baseline Results From the ACHIEVE Trial

BACKGROUND: Hearing loss is associated with restricted physical activity (PA) and impaired physical functioning, yet the relationship between severity of hearing impairment (HI) and novel PA measures in older adults with untreated HI is not well understood. METHODS: Analyses included 845 participants aged ≥70 years (mean = 76.6 years) with a better-hearing ear pure-tone average (PTA) ≥30 and &lt;70 dB in the Aging and Cognitive Health Evaluation in Elders (ACHIEVE) study who wore an ActiGraph accelerometer for 7 days. Physical functioning measures included grip strength and the Short Physical Performance Battery (SPPB). Linear regression models estimated the association by HI level (moderate or greater [PTA ≥ 40 dB] vs mild [PTA &lt; 40 dB]) and continuous hearing with total daily activity counts, active minutes/day, activity fragmentation, grip strength, and gait speed. Logistic regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs) of poor performance on the SPPB (≤6) and its subtests (≤2). Mixed-effects models estimated differences by HI level in activity by time of day. RESULTS: Participants with moderate or greater HI had poorer physical functioning, particularly balance (OR = 2.17, 95% CI = 1.29-3.67), versus those with mild impairment. There was no association of HI level with activity quantities or fragmentation. For diurnal patterns of activity, participants with moderate or greater HI had fewer activity counts in the afternoon (12:00 pm -05:59 pm). CONCLUSIONS: Older adults with worse hearing had shifted diurnal patterns and poorer balance performance. Exercise programs should be tailored to older adults with different levels of HI to maintain PA and physical functioning, particularly balance control

Surveillance study of apparent life-threatening events (ALTE) in the Netherlands

SIDS and ALTE are different entities that somehow show some similarities. Both constitute heterogeneous conditions. The Netherlands is a low-incidence country for SIDS. To study whether the same would hold for ALTE, we studied the incidence, etiology, and current treatment of ALTE in The Netherlands. Using the Dutch Pediatric Surveillance Unit, pediatricians working in second- and third-level hospitals in the Netherlands were asked to report any case of ALTE presented in their hospital from January 2002 to January 2003. A questionnaire was subsequently sent to collect personal data, data on pregnancy and birth, condition preceding the incident, the incident itself, condition after the incident, investigations performed, monitoring or treatment initiated during admission, any diagnosis made at discharge, and treatment or parental support offered after discharge. A total of 115 cases of ALTE were reported, of which 110 questionnaires were filled in and returned (response rate 97%). Based on the national birth rate of 200,000, the incidence of ALTE amounted 0.58/1,000 live born infants. No deaths occurred. Clinical diagnoses could be assessed in 58.2%. Most frequent diagnoses were (percentages of the total of 110 cases) gastro-esophageal reflux and respiratory tract infection (37.3% and 8.2%, respectively); main symptoms were change of color and muscle tone, choking, and gagging. The differences in diagnoses are heterogeneous. In 34%, parents shook their infants, which is alarmingly high. Pre- and postmature infants were overrepresented in this survey (29.5% and 8.2%, respectively). Ten percent had recurrent ALTE. In total, 15.5% of the infants were discharged with a home monitor. In conclusion, ALTE has a low incidence in second- and third-level hospitals in the Netherlands. Parents should be systematically informed about the possible devastating effects of shaking an infant. Careful history taking and targeted additional investigations are of utmost importance