Regulation of Synaptic Pumilio Function by an Aggregation-Prone Domain

We identified Pumilio (Pum), a Drosophila translational repressor, in a computational search for metazoan proteins whose activities might be regulated by assembly into ordered aggregates. The search algorithm was based on evolutionary sequence conservation patterns observed for yeast prion proteins, which contain aggregation-prone glutamine/asparagine (Q/N)-rich domains attached to functional domains of normal amino acid composition. We examined aggregation of Pum and its nematode ortholog PUF-9 by expression in yeast. A domain of Pum containing the Q/N-rich sequence, denoted as NQ1, the entire Pum N terminus, and the complete PUF-9 protein localize to macroscopic aggregates (foci) in yeast. NQ1 and PUF-9 can generate the yeast Pin+ trait, which is transmitted by a heritable aggregate. NQ1 also assembles into amyloid fibrils in vitro. In Drosophila, Pum regulates postsynaptic translation at neuromuscular junctions (NMJs). To assess whether NQ1 affects synaptic Pum activity in vivo, we expressed it in muscles. We found that it negatively regulates endogenous Pum, producing gene dosage-dependent pum loss-of-function NMJ phenotypes. NQ1 coexpression also suppresses lethality and NMJ phenotypes caused by overexpression of Pum in muscles. The Q/N block of NQ1 is required for these phenotypic effects. Negative regulation of Pum by NQ1 might be explained by formation of inactive aggregates, but we have been unable to demonstrate that NQ1 aggregates in Drosophila. NQ1 could also regulate Pum by a "dominant-negative" effect, in which it would block Q/N-mediated interactions of Pum with itself or with cofactors required for translational repression

Mononeuritis multiplex: an unexpectedly frequent feature of severe COVID-19

The prolonged mechanical ventilation that is often required by patients with severe COVID-19 is expected to result in significant Intensive Care Unit – Acquired Weakness (ICUAW) in many of the survivors. However, in our post-COVID-19 follow up clinic we have found that, as well as the anticipated global weakness related to loss of muscle mass, a significant proportion of these patients also have disabling focal neurological deficits relating to multiple axonal mononeuropathies. Amongst the 69 patients with severe COVID-19 that have been discharged from the intensive care units in our hospital, we have seen 11 individuals (16%) with such a mononeuritis multiplex. In many instances, the multi-focal nature of the weakness in these patients was initially unrecognised as symptoms were wrongly assumed to relate simply to “critical illness neuromyopathy”. While mononeuropathy is well recognised as an occasional complication of intensive care, our experience suggests that such deficits are surprisingly frequent and often disabling in patients recovering from severe COVID-19.Cambridge NIHR Biomedical Reseach Centr

Public private partnerships in tourism - a case study of Kerala Travel Mart

This paper highlights the public private partnership nature of the Kerala Travel Mart ( KTM) , a tourism trade show held in Kerala,India. The objective is to apply the theoretical framework from literature to analyse the effectiveness of the public private participatory nature of KTM. A case study approach has been adopted based on secondary data from Government records and from data compiled from KTM. KTM has been found to be a successful model for Public Private Partnership although there are some areas for improvement. This is the first such research study on the PPP nature of a collaborative venture in a destination which can be replicated by other destinations

Seasonal occurrence of potential fishing zones along northern Andhra Pradesh coast

228-232Data on potential fishing zones (PFZ), obtained from the Indian National Centre for Ocean Information Services (INCOIS), Hyderabad, and advisories for North Andhra coast were segregated season wise and analyzed to understand the trends and the frequency of occurrences of PFZ in North Andhra coast. Plotting of data revealed location of PFZ near coastal regions during summer months. These zones moved towards deeper waters during pre-monsoon, expanding to a larger area as the monsoon progressed and moved north during post-monsoon season. Plotting also revealed that Kakinada waters have frequent PFZ hits especially nearer to the Kakinada bay. Visakhapatnam waters were observed to get high intensity of PFZ hits during Monsoon followed by those during post-monsoon and summer seasons. However in Kalingapatnam waters, high intensity of PFZ occurred during post-monsoon followed by monsoon and summer seasons

Intervention Design Elements Are Associated with Frontline Health Workers\u27 Performance to Deliver Infant and Young Child Nutrition Services in Bangladesh and Vietnam

Background: Frontline health workers (FLWs) are needed for delivering interventions at scale to reduce maternal and child undernutrition, but low- and middle-income countries often face inadequate FLW performance.Objectives: We examined whether and how intervention design elements such as training, supervision, and mass media improved FLW performance in delivering nutrition services.Methods: Survey data were collected in 2010 and 2014 as part of impact evaluations of Alive & Thrive (A&T) interventions to improve infant and young child feeding (IYCF) practices in Bangladesh and Vietnam. FLWs in A&T intensive (A&T-I) areas received specialized IYCF training, job aids, and regular supportive supervision. Those in non-intensive (A&T-NI) areas received standard government training and supervision. There was mass media exposure in both areas. Multiple regression was used to test differences in exposure to intervention design elements and performance outcomes between the 2 program areas. Path analyses were conducted to examine the paths from exposure to performance outcomes measured at FLW and end-user levels.Results: Compared to FLWs in A&T-NI areas, those in A&T-I areas had higher scores in training (by 1.3-3.6 of 10 points), supportive supervision (0.3-3.5 points), and mass media exposure (0.3-3.5 points). These intervention design elements were significantly associated with FLW knowledge and motivation, which in turn improved service delivery. FLW-level performance outcomes contributed to improving end-user-level outcomes such as higher service received (beta = 0.12-1.04 in Bangladesh and 0.11-0.96 in Vietnam) and maternal knowledge (beta = 0.12-0.17 in Bangladesh and 0.04-0.21 in Vietnam).Conclusions: Training, supervision, and mass media exposure can be implemented at large scale and contribute to improved FLW service delivery by enhancing knowledge and motivation, which in turn positively influence mother\u27s service utilization and IYCF knowledge. Training, supervision, and mass media to enhance service provision should be considered when designing interventions. This trial was registered at clinicaltrials.gov as NCT01678716 (Bangladesh) and NCT01676623 (Vietnam)

Environmental Sustainability in the Follow-Up and Evaluation Stage of Logistics Services Purchasing: Perspectives from UK Shippers and 3PLs

The purpose of the research described in this paper is to investigate the role played by the green agenda and sustainability in the follow-up and evaluation stage of the purchasing of logistics services. This stage is relatively under-explored in the extant academic literature. However, there is some evidence of a divergence between the perspectives of shippers and forwarders in this area. In this context, therefore, two carefully selected groups of UK-based supply chain management professionals—from shippers (i.e., manufacturers and retailers) and third-party logistics (3PLs)—were investigated using semi-structured interviews. The interviews were based on a data collection guide informed by the authors’ three overall research objectives. Data from the interviews were analysed using a combination of content analysis and grounded analysis. The findings suggest that, while shippers and 3PLs recognise a positive link between cost savings and the development of green initiatives, there is considerable room for improvement in this area in order to reorient the focus of the follow-up and evaluation stage from price and service levels towards sustainability. The authors’ exploratory research leads to the identification of a number of potentially fruitful areas for future research

Genomic Classifier Augments the Role of Pathological Features in Identifying Optimal Candidates for Adjuvant Radiation Therapy in Patients With Prostate Cancer: Development and Internal Validation of a Multivariable Prognostic Model.

Purpose Despite documented oncologic benefit, use of postoperative adjuvant radiotherapy (aRT) in patients with prostate cancer is still limited in the United States. We aimed to develop and internally validate a risk-stratification tool incorporating the Decipher score, along with routinely available clinicopathologic features, to identify patients who would benefit the most from aRT. Patient and Methods Our cohort included 512 patients with prostate cancer treated with radical prostatectomy at one of four US academic centers between 1990 and 2010. All patients had ≥ pT3a disease, positive surgical margins, and/or pathologic lymph node invasion. Multivariable Cox regression analysis tested the relationship between available predictors (including Decipher score) and clinical recurrence (CR), which were then used to develop a novel risk-stratification tool. Our study adhered to the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis guidelines for development of prognostic models. Results Overall, 21.9% of patients received aRT. Median follow-up in censored patients was 8.3 years. The 10-year CR rate was 4.9% vs. 17.4% in patients treated with aRT versus initial observation ( P \u3c .001). Pathologic T3b/T4 stage, Gleason score 8-10, lymph node invasion, and Decipher score \u3e 0.6 were independent predictors of CR (all P \u3c .01). The cumulative number of risk factors was 0, 1, 2, and 3 to 4 in 46.5%, 28.9%, 17.2%, and 7.4% of patients, respectively. aRT was associated with decreased CR rate in patients with two or more risk factors (10-year CR rate 10.1% in aRT v 42.1% in initial observation; P = .012), but not in those with fewer than two risk factors ( P = .18). Conclusion Using the new model to indicate aRT might reduce overtreatment, decrease unnecessary adverse effects, and reduce risk of CR in the subset of patients (approximately 25% of all patients with aggressive pathologic disease in our cohort) who benefit from this therapy

Nutrition Intervention Using Behavioral Change Communication Without Additional Material Inputs Increased Expenditures on Key Food Groups in Bangladesh

Background Behavioral change communication (BCC) promotes skills and knowledge to improve infant and young child feeding, but without additional material inputs, recipients must develop strategies to translate knowledge into action. Using data from the Alive & Thrive initiative in Bangladesh (2010–2014), we aimed to test whether households receiving the intensive intervention (opposed to the nonintensive intervention) increased expenditures on key foods for mothers and children (e.g., foods that were promoted by the intervention and also changed in maternal and child diets). Methods The intensive intervention provided interpersonal counseling, community mobilization, and mass media campaigns to promote breastfeeding and complementary feeding. A cluster-randomized design compared 20 subdistricts randomly assigned to the intensive (4281 households) or nonintensive (4284 households) intervention. Measures included food and nonfood expenditures, dietary diversity, and women\u27s economic resources. Linear and logistic regression tested difference-in-differences (DD) in expenditures and dietary diversity, accounting for subdistricts as clusters, and the association between maternal and child consumption of specific food groups and corresponding food expenditures. Results Expenditures on eggs and flesh foods increased more in intensive areas than in nonintensive areas by 53 (P \u3c 0.01) and 471 (P \u3c 0.01) taka/mo, respectively. Household food expenditures increased more in intensive areas by 832 taka (P = 0.02), whereas changes in nonfood expenditures did not differ. Women\u27s employment and control of income increased more in intensive areas by 12 (P = 0.03) and 13 (P \u3c 0.01) percentage points, respectively, while jewelry ownership decreased more by 23 percentage points (P \u3c 0.01). Higher expenditures on food groups were reflected in higher consumption by women and children. Conclusions Recipients in the intensive intervention mobilized additional resources to improve diets, reflected in increased expenditures and consumption of promoted foods. BCC interventions should document how recipients produce desired results without additional material inputs, particularly for behaviors that likely require additional resources. This trial was registered at clinicaltrials.gov as NCT01678716

Cerebral Perfusion Pressure Targets Individualized to Pressure-Reactivity Index in Moderate to Severe Traumatic Brain Injury: A Systematic Review.

Traumatic brain injury (TBI) frequently triggers a disruption of cerebral autoregulation. The cerebral perfusion pressure (CPP) at which autoregulation is optimal ("CPPopt") varies between individuals, and can be calculated based on fluctuations between arterial blood pressure and intracranial pressure. This review assesses the effect of individualizing CPP targets to pressure reactivity index (a measure of autoregulation) in patients with TBI. Cochrane Central Register of Controlled Trials, MEDLINE®, Embase, and Cumulative Index of Nursing and Allied Health Literature were searched in March 2015 for studies assessing the effect of targeting CPPopt in TBI. We included all studies that assessed the impact of targeting CPPopt on outcomes including mortality, neurological outcome, and physiological changes. Risk of bias was assessed using the RTI Item Bank and evidence quality was considered using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. Eight cohort studies (based on six distinct data sets) assessing the association between CPPopt and mortality, Glasgow Outcome Scale and physiological measures in TBI were included. The quality of evidence was deemed very low based on the GRADE criteria. Although the data suggest an association between variation from CPPopt and poor clinical outcome at 6 months, the quality of evidence prevents firm conclusions, particularly regarding causality, from being drawn. Available data suggest that targeting CPPopt might represent a technique to improve outcomes following TBI, but currently there is insufficient high-quality data to support a recommendation for use in clinical practice. Further prospective, randomized controlled studies should be undertaken to clarify its role in the acute management of TBI.This is the author accepted manuscript. The final version is available from MAry Ann Liebert via http://dx.doi.org/10.1089/neu.2016.445