Changes in Purkinje cell firing and gene expression precede behavioral pathology in a mouse model of SCA2.

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominantly inherited disorder, which is caused by a pathological expansion of a polyglutamine (polyQ) tract in the coding region of the ATXN2 gene. Like other ataxias, SCA2 most overtly affects Purkinje cells (PCs) in the cerebellum. Using a transgenic mouse model expressing a full-length ATXN2(Q127)-complementary DNA under control of the Pcp2 promoter (a PC-specific promoter), we examined the time course of behavioral, morphologic, biochemical and physiological changes with particular attention to PC firing in the cerebellar slice. Although motor performance began to deteriorate at 8 weeks of age, reductions in PC number were not seen until after 12 weeks. Decreases in the PC firing frequency first showed at 6 weeks and paralleled deterioration of motor performance with progression of disease. Transcription changes in several PC-specific genes such as Calb1 and Pcp2 mirrored the time course of changes in PC physiology with calbindin-28 K changes showing the first small, but significant decreases at 4 weeks. These results emphasize that in this model of SCA2, physiological and behavioral phenotypes precede morphological changes by several weeks and provide a rationale for future studies examining the effects of restoration of firing frequency on motor function and prevention of future loss of PCs

Decline in coral cover and flattening of the reefs around Mauritius (1998–2010)

© The Author(s), 2018. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Elliott JA, Patterson MR, Staub CG, Koonjul M, Elliott SM. 2018. Decline in coral cover and flattening of the reefs around Mauritius (1998–2010) PeerJ 6:e6014, doi: 10.7717/peerj.6014 .Coral reefs are degrading through the impacts of multiple anthropogenic stressors. How are coral reef communities going to change and how to protect them for future generations are important conservation questions. Using coral reef data from Mauritius, we examined changes in cover in 23 benthic groups for a 13-yr period and at 15 sites. Moreover, we determined which land-based stressor out of four (human population, agriculture, tourism, rainfall) correlated the most with the observed changes in coral reef cover. Among the stony corals, Acropora corals appeared to be the most impacted, decreasing in cover at many sites. However, the non-Acropora encrusting group increased in cover at several sites. The increase in abundance of dead corals and rubble at some sites also supported the observations of stony coral decline during the study period. Additionally, the decline in stony corals appeared to be more pronounced in second half of the study period for all sites suggesting that a global factor rather than a local factor was responsible for this decline. There was little change in cover for the other benthic groups, some of which were quite rare. Human population was significantly correlated with changes in coral reef cover for 11 sites, followed by tourism and agriculture. Rainfall, a proxy for runoff, did not appear to affect coral reef cover. Overall, our results showed that there has been a decline of stony coral cover especially the ones with complex morphologies, which in turn suggest that coral reefs around Mauritius have experienced a decline in habitat complexity during the study period. Our study also suggests that humans are an important factor contributing to the demise of coral reefs around the island.We would like to thank the Albion Fisheries Research Centre, Ministry of Fisheries, Government of Mauritius for providing the long-term benthic community dataset without which this work would not have been possible. Jennifer Elliott expresses her deepest gratitude to the members of her advisory committee, Peter Edmunds, Tarik Gouhier, Brian Helmuth and Steve Vollmer for their thoughtful inputs during the execution of this work. This is contribution number 384 from the Marine Science Center at Northeastern University

Double-blind, placebo-controlled, randomized trial of octreotide in malignant bowel obstruction

Context Does octreotide reduce vomiting in cancer-associated bowel obstruction? Objectives To evaluate the net effect of adding octreotide or placebo to standardized therapies on the number of days free of vomiting for populations presenting with vomiting and inoperable bowel obstruction secondary to cancer or its treatment. Methods Twelve services enrolled people with advanced cancer presenting with vomiting secondary to bowel obstruction where surgery or anti-cancer therapies were not indicated immediately. In a double-blind study, participants were randomized to placebo or octreotide (600 μg/24 hours by infusion). Both arms received standardized supportive therapy (infusion of ranitidine [200 mg/24 hours], dexamethasone [8 mg/24 hours], and parenteral hydration [10-20 mL/kg/24 hours]). The primary outcome was patient-reported days free of vomiting at 72 hours. Results In a study that recruited to the numbers identified in its power calculation, 87 participants provided data at 72 hours (45, octreotide arm). Seventeen people (octreotide) and 14 (placebo) were free of vomiting for 72 hours (P = 0.67). Mean days free of vomiting were 1.87 (SD 1.10; octreotide) and 1.69 (SD 1.15; placebo; P = 0.47). An adjusted multivariate regression of the incidence of vomiting over the study showed a reduced number of episodes of vomiting in the octreotide group (incidence rate ratio = 0.40; 95% CI: 0.19-0.86; P = 0.019); however, people in the octreotide arm were 2.02 times more likely to be administered hyoscine butylbromide (P = 0.004), potentially reflecting increased colicky pain. Conclusion Although there was no reduction in the number of days free of vomiting, the multivariate analysis suggests that further study of somatostatin analogues in this setting is warranted

Examining impulsivity as an endophenotype using a behavioral approach: a DRD2 TaqI A and DRD4 48-bp VNTR association study

BACKGROUND: Research on the genetic basis for impulsivity has revealed an array of ambiguous findings. This may be a result of limitations to self-report assessments of impulsivity. Behavioral measures that assess more narrowly defined aspects of impulsivity may clarify genetic influences. This study examined the relationship between possession of the DRD2 TaqI A and DRD4 48 bp VNTR genetic polymorphisms and performance on a behavioral measure of impulsivity, the delay discounting task (DDT), and three traditional self-report measures. METHODS: 195 individuals (42% male) were recruited from a university campus and were assessed in small group sessions using personal computers. Genotyping was conducted using previously established protocols. For the DRD2 TaqI A locus, individuals were designated as possessing at least one copy of the A1 allele (A1+) or not (A1-), and for the DRD4 48-bp VNTR locus, individuals were designated as having at least one long allele (7 repeats or longer, L+) or not (L-). Principal analyses used multiple univariate factorial 2 (A1+/A1-) × 2 (L+/L-) analyses of variance. RESULTS: A significant main effect of A1+ status on DDT performance was evident (p = .006) as well as a significant interaction effect (p = .006) between both genes. No other significant effects were evident on the self-report measures, with the exception of a trend toward an interaction effect on the Sensation Seeking Scale. Exploratory analyses suggested that the significant effects were not a function of population stratification or gender. DISCUSSION: These data suggest that the DRD2 TaqI A and DRD4 VNTR polymorphisms influence impulsivity as measured with a delay discounting task. Specifically, these findings suggest that an interaction between the functional effects of the two unlinked genotypes results in significant difference in the balance of mesolimbic dopaminergic activation relative to frontal-parietal activation. However, these findings are also the first in this area and must be replicated. CONCLUSION: These findings suggest a meaningful interaction between the DRD2 TaqI A and DRD4 VNTR polymorphisms in the expression of impulsivity and provide initial support for the utility of using behavioral measures for clarifying genetic influences on impulsivity

Clinicians\u27 delirium treatment practice, practice change, and influences: A national online survey

Background: Recent studies cast doubt on the net effect of antipsychotics for delirium. Aim: To investigate the influence of these studies and other factors on clinicians’ delirium treatment practice and practice change in palliative care and other specialties using the Theoretical Domains Framework. Design: Australia-wide online survey of relevant clinicians. Setting/participants: Registered nurses (72%), doctors (16%), nurse practitioners (6%) and pharmacists (5%) who cared for patients with delirium in diverse settings, recruited through health professionals’ organisations. Results: Most of the sample (n=475): worked in geriatrics/aged (31%) or palliative care (30%); in hospitals (64%); and saw a new patient with delirium at least weekly (61%). More (59%) reported delirium practice change since 2016, mostly by increased non-pharmacological interventions (53%). Fifty-five percent reported current antipsychotic use for delirium, primarily for patient distress (79%) and unsafe behaviour (67%). Common Theoretical Domains Framework categories of influences on respondents’ delirium practice were: emotion (54%); knowledge (53%) and physical (43%) and social (21%) opportunities. Palliative care respondents more often reported: awareness of any named key study of antipsychotics for delirium (73% vs 39%, p\u3c0.001); decreased pharmacological interventions (60% vs 15%, p\u3c0.001); off-label medication use (86% vs 51%, p\u3c0.001); antipsychotics 79% vs 44%, p\u3c0.001); benzodiazepines 61% vs 26%, p\u3c0.001); and emotion as an influence (82% vs 39%, p\u3c0.001). Conclusion: Clinicians’ use of antipsychotic during delirium remains common and is primarily motivated by distress and safety concerns for the patient and others nearby. Supporting clinicians to achieve evidence-based delirium practice requires further work

Compliance with referrals for non-acute child health conditions: evidence from the longitudinal ASENZE study in KwaZulu Natal, South Africa

Background: Caregiver compliance with referrals for child health services is essential to child health outcomes. Many studies in sub-Saharan Africa have examined compliance patterns for children referred for acute, life-threatening conditions but few for children referred for non-acute conditions. The aims of this analysis were to determine the rate of referral compliance and investigate factors associated with referral compliance in KwaZulu Natal, South Africa. Methods: From September 2008–2010, a door-to-door household survey was conducted to identify children aged 4–6 years in outer-west eThekwini District, KwaZulu-Natal, South Africa. Of 2,049 identified, informed consent was obtained for 1787 (89%) children who were then invited for baseline assessments. 1581 children received standardized medical and developmental assessments at the study facility (Phase 1). Children with anemia, suspected disorders of vision, hearing, behavior and/or development and positive HIV testing were referred to local health facilities. Caregiver-reported compliance with referrals was assessed 18–24 months later (Phase 2). Relationships between socio-demographic factors and referral compliance were evaluated using chi-square tests. Results: Of 1581 children, 516 received referrals for ≥1 non-acute conditions. At the time of analysis, 68% (1078 /1581) returned for Phase 2. Analysis was limited to children assessed in Phase 2 who received a referral in Phase 1 (n = 303). Common referral reasons were suspected disorders of hearing/middle ear (22%), visual acuity (12%) and anemia (14%). Additionally, children testing positive for HIV (6.6%) were also referred. Of 303 children referred, only 45% completed referrals. Referral compliance was low for suspected disorders of vision, hearing and development. Referral compliance was significantly lower for children with younger caregivers, those living in households with low educational attainment and for those with unstable caregiving. Conclusions: Compliance with referrals for children with non-acute conditions is low within this population and appears to be influenced by caregiver age, household education level and stability of caregiving. Lack of treatment for hearing, vision and developmental problems can contribute to long-term cognitive difficulties. Further research is underway by this group to examine caregiver knowledge and attitudes about referral conditions and health system characteristics as potential determinants of referral compliance

Gender Dependence for a Subset of the Low-Abundance Signaling Proteome in Human Platelets

The incidence of cardiovascular diseases is ten-times higher in males than females, although the biological basis for this gender disparity is not known. However, based on the fact that antiplatelet drugs are the mainstay for prevention and therapy, we hypothesized that the signaling proteomes in platelets from normal male donors might be more activated than platelets from normal female donors. We report here that platelets from male donors express significantly higher levels of signaling cascade proteins than platelets from female donors. In silico connectivity analysis shows that the 24 major hubs in platelets from male donors focus on pathways associated with megakaryocytic expansion and platelet activation. By contrast, the 11 major hubs in platelets from female donors were found to be either negative or neutral for platelet-relevant processes. The difference may suggest a biological mechanism for gender discrimination in cardiovascular disease

Global access to surgical care: a modelling study

Background More than 2 billion people are unable to receive surgical care based on operating theatre density alone. The vision of the Lancet Commission on Global Surgery is universal access to safe, aff ordable surgical and anaesthesia care when needed. We aimed to estimate the number of individuals worldwide without access to surgical services as defi ned by the Commission’s vision. Methods We modelled access to surgical services in 196 countries with respect to four dimensions: timeliness, surgical capacity, safety, and aff ordability. We built a chance tree for each country to model the probability of surgical access with respect to each dimension, and from this we constructed a statistical model to estimate the proportion of the population in each country that does not have access to surgical services. We accounted for uncertainty with oneway sensitivity analyses, multiple imputation for missing data, and probabilistic sensitivity analysis. Findings At least 4·8 billion people (95% posterior credible interval 4·6–5·0 [67%, 64–70]) of the world’s population do not have access to surgery. The proportion of the population without access varied widely when stratifi ed by epidemiological region: greater than 95% of the population in south Asia and central, eastern, and western sub- Saharan Africa do not have access to care, whereas less than 5% of the population in Australasia, high-income North America, and western Europe lack access. Interpretation Most of the world’s population does not have access to surgical care, and access is inequitably distributed. The near absence of access in many low-income and middle-income countries represents a crisis, and as the global health community continues to support the advancement of universal health coverage, increasing access to surgical services will play a central role in ensuring health care for all

Pharmacovigilance in hospice/palliative care: the net immediate and short-term effects of dexamethasone for anorexia

Objectives Loss of appetite is prevalent in palliative care and distressing for patients and families. Therapies include corticosteroids or progestogens. This study explores the net effect of dexamethasone on anorexia. Methods Prospective data were collected when dexamethasone was started for anorexia as part of routine care. The National Cancer Institute’s Common Toxicity Criteria for Adverse Events (NCICTCAE) Likert scales assessed severity of anorexia and immediate and short-term harms at 2 time points: baseline and 7 days. Results This study (41 sites, 8 countries) collected data (July 2013 to July 2014) from 114 patients (mean age 71 (SD 11), 96% with cancer). Median Australian-modified Karnofsky Performance Scale was 50% (range 20–70). Mean baseline NCICTCAE anorexia score was 2.7 (SD 0.6; median 3). 6 patients died by day 7. Of 108 evaluable patients, 74 (68.5%; 95% CI 59.0% to 76.7%) reported ≥1 reduction anorexia scores by day 7, of whom 30 were 0. Mean dexamethasone dose on day 7 was 4.1 mg/day (SD 3.4; median 4; range 0–46 mg). 24 patients reported ≥1 harms (32.4% CI 22.6% to 44.1%; insomnia n=10, depression n=7, euphoria n=7 and hyperglycaemia n=7). Of 24 patients with no benefit, 10 reported ≥1 harms. Conclusions This study shows positive and negative effects of 7 days of dexamethasone as an appetite stimulant in patients with advanced life-limiting illnesses. Identifying clinicodemographic characteristics of people most at risk of harms with no benefit is a crucial next step. Longer term follow-up will help to understand longer term and cumulative harms

Immunotherapy with CD25/CD71-allodepleted T cells to improve T-cell reconstitution after matched unrelated donor hematopoietic stem cell transplant: a randomized trial

BACKGROUND AND AIMS: Delayed immune reconstitution is a major challenge after matched unrelated donor (MUD) stem cell transplant (SCT). In this randomized phase 2 multi-center trial, Adoptive Immunotherapy with CD25/71 allodepleted donor T cells to improve immunity after unrelated donor stem cell transplant (NCT01827579), the authors tested whether allodepleted donor T cells (ADTs) can safely be used to improve immune reconstitution after alemtuzumab-based MUD SCT for hematological malignancies. METHODS: Patients received standard of care or up to three escalating doses of ADTs generated through CD25+/CD71+ immunomagnetic depletion. The primary endpoint of the study was circulating CD3+ T-cell count at 4 months post-SCT. Twenty-one patients were treated, 13 in the ADT arm and eight in the control arm. RESULTS: The authors observed a trend toward improved CD3+ T-cell count at 4 months in the ADT arm versus the control arm (230/µL versus 145/µL, P = 0.18), and three ADT patients achieved normal CD3+ T-cell count at 4 months (>700/µL). The rates of significant graft-versus-host disease (GVHD) were comparable in both cohorts, with grade ≥2 acute GVHD in seven of 13 and four of eight patients and chronic GVHD in three of 13 and three of eight patients in the ADT and control arms, respectively. CONCLUSIONS: These data suggest that adoptive transfer of ADTs is safe, but that in the MUD setting the benefit in terms of T-cell reconstitution is limited. This approach may be of more use in the context of more rigorous T-cell depletion