Retrospective harm benefit analysis of pre-clinical animal research for six treatment interventions

The harm benefit analysis (HBA) is the cornerstone of animal research regulation and is considered to be a key ethical safeguard for animals. The HBA involves weighing the anticipated benefits of animal research against its predicted harms to animals but there are doubts about how objective and accountable this process is.i. To explore the harms to animals involved in pre-clinical animal studies and to assess these against the benefits for humans accruing from these studies; ii. To test the feasibility of conducting this type of retrospective HBA.Data on harms were systematically extracted from a sample of pre-clinical animal studies whose clinical relevance had already been investigated by comparing systematic reviews of the animal studies with systematic reviews of human studies for the same interventions (antifibrinolytics for haemorrhage, bisphosphonates for osteoporosis, corticosteroids for brain injury, Tirilazad for stroke, antenatal corticosteroids for neonatal respiratory distress and thrombolytics for stroke). Clinical relevance was also explored in terms of current clinical practice. Harms were categorised for severity using an expert panel. The quality of the research and its impact were considered. Bateson's Cube was used to conduct the HBA.The most common assessment of animal harms by the expert panel was 'severe'. Reported use of analgesia was rare and some animals (including most neonates) endured significant procedures with no, or only light, anaesthesia reported. Some animals suffered iatrogenic harms. Many were kept alive for long periods post-experimentally but only 1% of studies reported post-operative care. A third of studies reported that some animals died prior to endpoints. All the studies were of poor quality. Having weighed the actual harms to animals against the actual clinical benefits accruing from these studies, and taking into account the quality of the research and its impact, less than 7% of the studies were permissible according to Bateson's Cube: only the moderate bisphosphonate studies appeared to minimise harms to animals whilst being associated with benefit for humans.This is the first time the accountability of the HBA has been systematically explored across a range of pre-clinical animal studies. The regulatory systems in place when these studies were conducted failed to safeguard animals from severe suffering or to ensure that only beneficial, scientifically rigorous research was conducted. Our findings indicate a pressing need to: i. review regulations, particularly those that permit animals to suffer severe harms; ii. reform the processes of prospectively assessing pre-clinical animal studies to make them fit for purpose; and iii. systematically evaluate the benefits of pre-clinical animal research to permit a more realistic assessment of its likely future benefits

Effects of recombinant LH supplementation to recombinant FSH during induced ovarian stimulation in the GnRH-agonist protocol: a matched case-control study

<p>Abstract</p> <p>Background</p> <p>Some studies have suggested that the suppression of endogenous LH secretion does not seem to affect the majority of patients who are undergoing assisted reproduction and stimulation with recombinant FSH (r-FSH). Other studies have indicated that a group of normogonadotrophic women down-regulated and stimulated with pure FSH preparations may experience low LH concentrations that compromise the IVF parameters. The present study aimed to compare the efficacy of recombinant LH (r-LH) supplementation for controlled ovarian stimulation in r-FSH and GnRH-agonist (GnRH-a) protocol in ICSI cycles.</p> <p>Methods</p> <p>A total of 244 patients without ovulatory dysfunction, aged <40 years and at the first ICSI cycle were divided into two groups matched by age according to an ovarian stimulation scheme: Group I (n = 122): Down-regulation with GnRH-a + r-FSH and Group II (n = 122): Down-regulation with GnRH-a + r-FSH and r-LH (beginning simultaneously).</p> <p>Result(s)</p> <p>The number of oocytes collected, the number of oocytes in metaphase II and fertilization rate were significantly lower in the Group I than in Group II (<it>P </it>= 0.036, <it>P </it>= 0.0014 and <it>P </it>= 0.017, respectively). In addition, the mean number of embryos produced per cycle and the mean number of frozen embryos per cycle were statistically lower (<it>P </it>= 0.0092 and <it>P </it>= 0.0008, respectively) in Group I than in Group II. Finally the cumulative implantation rate (fresh+thaw ed embryos) was significantly lower (<it>P </it>= 0.04) in Group I than in Group II. The other clinical and laboratory results analyzed did not show difference between groups.</p> <p>Conclusion</p> <p>These data support r-LH supplementation in ovarian stimulation protocols with r-FSH and GnRH-a for assisted reproduction treatment.</p

Quaternary structure of a G-protein coupled receptor heterotetramer in complex with Gi and Gs

Background: G-protein-coupled receptors (GPCRs), in the form of monomers or homodimers that bind heterotrimeric G proteins, are fundamental in the transfer of extracellular stimuli to intracellular signaling pathways. Different GPCRs may also interact to form heteromers that are novel signaling units. Despite the exponential growth in the number of solved GPCR crystal structures, the structural properties of heteromers remain unknown. Results: We used single-particle tracking experiments in cells expressing functional adenosine A1-A2A receptors fused to fluorescent proteins to show the loss of Brownian movement of the A1 receptor in the presence of the A2A receptor, and a preponderance of cell surface 2:2 receptor heteromers (dimer of dimers). Using computer modeling, aided by bioluminescence resonance energy transfer assays to monitor receptor homomerization and heteromerization and G-protein coupling, we predict the interacting interfaces and propose a quaternary structure of the GPCR tetramer in complex with two G proteins. Conclusions: The combination of results points to a molecular architecture formed by a rhombus-shaped heterotetramer, which is bound to two different interacting heterotrimeric G proteins (Gi and Gs). These novel results constitute an important advance in understanding the molecular intricacies involved in GPCR function

International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee Report on Inborn Errors of Immunity

Beginning in 1970, a committee was constituted under the auspices of the World Health Organization (WHO) to catalog primary immunodeficiencies. Twenty years later, the International Union of Immunological Societies (IUIS) took the remit of this committee. The current report details the categorization and listing of 354 (as of February 2017) inborn errors of immunity. The growth and increasing complexity of the field have been impressive, encompassing an increasing variety of conditions, and the classification described here will serve as a critical reference for immunologists and researchers worldwide

A Filmless Radiology Department in a Full Digital Regional Hospital: Quantitative Evaluation of the Increased Quality and Efficiency

Reggio Emilia hospital installed Picture Archiving and Communications Systems (PACS) as the final step towards a completely digital clinical environment completing the HIS/EMR and 1,400 web/terminals for patient information access. Financial benefits throughout the hospital were assessed upfront and measured periodically. Key indicators (radiology exam turnaround time, number of radiology procedures performed, inpatients length of stay before and after the PACS implementation, etc.) were analyzed and values were statistically tested to assess workflow and productivity improvements. The hospital went “filmless” in 28 weeks. Between the half of 2004 and the respective period in 2003, overall Radiology Department productivity increased by 12%, TAT improved by more than 60%. Timelier patient care resulted in decreased lengths of stay. Neurology alone experienced a 12% improvement in average patient stay. To quantify the impact of PACS on the average hospital stays and the expected productivity benefits to inpatient productivity were used a “high level” and a “detailed” business model. Annual financial upsides have exceeded $1.9 millions/year. A well-planned PACS deployment simplifies imaging workflow and improves patient care throughout the hospital while delivering substantial financial benefits. Staff buy-in was the key in this process and on-going training and process monitoring are a must

Motivation and job satisfaction among medical and nursing staff in a Cyprus public general hospital

<p>Abstract</p> <p>Background</p> <p>The objective of this study was to investigate how medical and nursing staff of the Nicosia General Hospital is affected by specific motivation factors, and the association between <it>job satisfaction </it>and <it>motivation</it>. Furthermore, to determine the motivational drive of socio-demographic and job related factors in terms of improving work performance.</p> <p>Methods</p> <p>A previously developed and validated instrument addressing four work-related motivators (<it>job attributes, remuneration, co-workers and achievements</it>) was used. Two categories of health care professionals, medical doctors and dentists (N = 67) and nurses (N = 219) participated and motivation and job satisfaction was compared across socio-demographic and occupational variables.</p> <p>Results</p> <p>The survey revealed that <it>achievements </it>was ranked first among the four main motivators, followed by <it>remuneration</it>, <it>co-workers </it>and <it>job attributes</it>. The factor <it>remuneration </it>revealed statistically significant differences according to gender, and hospital sector, with female doctors and nurses and accident and emergency (A+E) outpatient doctors reporting greater mean scores (p < 0.005). The medical staff showed statistically significantly lower job satisfaction compared to the nursing staff. Surgical sector nurses and those >55 years of age reported higher job satisfaction when compared to the other groups.</p> <p>Conclusions</p> <p>The results are in agreement with the literature which focuses attention to management approaches employing both monetary and non-monetary incentives to motivate health care professionals. Health care professionals tend to be motivated more by intrinsic factors, implying that this should be a target for effective employee motivation. Strategies based on the survey's results to enhance employee motivation are suggested.</p

Holographic Vitrification

We establish the existence of stable and metastable stationary black hole bound states at finite temperature and chemical potentials in global and planar four-dimensional asymptotically anti-de Sitter space. We determine a number of features of their holographic duals and argue they represent structural glasses. We map out their thermodynamic landscape in the probe approximation, and show their relaxation dynamics exhibits logarithmic aging, with aging rates determined by the distribution of barriers.Comment: 100 pages, 25 figure

Impact of long-term viral suppression in CD4+ recovery of HIV-children on Highly Active Antiretroviral Therapy

BACKGROUND: The effects of HAART may differ between children and adults because children have a developing immune system, and the long-term immunological outcome in HIV-infected children on HAART is not well-known. A major aim of our study was to determine CD4+ evolution associated with long-term VL control during 4 years of observation on HAART. METHODS: We carried out a retrospective study on a cohort of 160 vertically HIV-infected children. It was carried out from 1996 to 2004 in six large Spanish pediatric referral hospitals. We compared 33 children who had long-term VL suppression (VL ≤400 copies/ml) in the first 12 months of follow-up and maintained that level throughout follow-up (Responders-group), and 127 children with persistently detectable VL in spite of ART switches (Non-Responders-group). RESULTS: We observed a quick initial and significant increase in CD4(+ )counts from the baseline to 12 months on HAART in both groups (p < 0.01). The Non-Responders group sustained CD4+ increases and most of these children maintained high CD4(+ )level counts (≥25%). The Non-Responders group reached a plateau between 26% and 27% CD4(+ )at the first 12 months of follow-up that remained stable during the following 3 years. However, the Responders group reached a plateau between 30% and 32% CD4(+ )at 24, 36 and 48 months of follow-up. We found that the Responders group had higher CD4(+ )count values and higher percentages of children with CD4(+ )≥25% than the Non-Responders group (p < 0.05) after month 12. CONCLUSION: Long-term VL suppression in turn induces large beneficial effects in immunological responses. However, it is not indispensable to recover CD4(+ )levels

Relative costs and effectiveness of treating uncomplicated malaria in two rural districts in Zambia: implications for nationwide scale-up of home-based management

<p>Abstract</p> <p>Background</p> <p>Malaria case management is one of the key strategies to control malaria. Various studies have demonstrated the feasibility of home management of malaria (HMM). However, data on the costs and effectiveness of artemisinin-based combination therapy (ACT) and rapid diagnostic tests via HMM is limited.</p> <p>Method</p> <p>Cost-effectiveness of home management versus health facility-based management of uncomplicated malaria in two rural districts in Zambia was analysed from a providers' perspective. The sample included 16 community health workers (CHWs) and 15 health facilities. The outcome measure was the cost per case appropriately diagnosed and treated. Costs of scaling-up HMM nationwide were estimated based on the CHW utilisation rates observed in the study.</p> <p>Results</p> <p>HMM was more cost effective than facility-based management of uncomplicated malaria. The cost per case correctly diagnosed and treated was USD 4.22 for HMM and USD 6.12 for facility level. Utilization and adherence to diagnostic and treatment guidelines was higher in HMM than at a health facility.</p> <p>Conclusion</p> <p>HMM using ACT and RDTs was more efficient at appropriately diagnosing and treating malaria than the health facility level. Scaling up this intervention requires significant investments.</p

The deuteron: structure and form factors

A brief review of the history of the discovery of the deuteron in provided. The current status of both experiment and theory for the elastic electron scattering is then presented.Comment: 80 pages, 33 figures, submited to Advances in Nuclear Physic