Deformation versus Sphericity in the Ground States of the Lightest Gold Isotopes.

The changes in mean-squared charge radii of neutron-deficient gold nuclei have been determined using the in-source, resonance-ionization laser spectroscopy technique, at the ISOLDE facility (CERN). From these new data, nuclear deformations are inferred, revealing a competition between deformed and spherical configurations. The isotopes ^{180,181,182}Au are observed to possess well-deformed ground states and, when moving to lighter masses, a sudden transition to near-spherical shapes is seen in the extremely neutron-deficient nuclides, ^{176,177,179}Au. A case of shape coexistence and shape staggering is identified in ^{178}Au which has a ground and isomeric state with different deformations. These new data reveal a pattern in ground-state deformation unique to the gold isotopes, whereby, when moving from the heavy to light masses, a plateau of well-deformed isotopes exists around the neutron midshell, flanked by near-spherical shapes in the heavier and lighter isotopes-a trend hitherto unseen elsewhere in the nuclear chart. The experimental charge radii are compared to those from Hartree-Fock-Bogoliubov calculations using the D1M Gogny interaction and configuration mixing between states of different deformation. The calculations are constrained by the known spins, parities, and magnetic moments of the ground states in gold nuclei and show a good agreement with the experimental results.

The need for cardiac surgery differential tariffs in Israel at the era of aging population and emerging technology: Importance of procedure type and patient complexity as assessed by EuroSCORE.

BACKGROUND: Reimbursement for cardiac surgical procedures in Israel is uniform and does not account for diversity in costs of various procedures or for diversity in patient mix. In an era of new and costly technology coupled with higher risk patients needing more complex surgery, these tariffs may not adequately reflect the true financial burden on the caregivers. In the present study we attempt to determine whether case mix and complexity of procedures significantly affect cost to justify differential tariffs. METHODS: We included all patients undergoing cardiac surgery at Shaare Zedek Medical Center between the years 1993-2016. Patients were stratified according to (1) type of surgery and (2) clinical profile as reflected by the predicted operative risk according to the European System for Cardiac Operative Risk Evaluation (EuroSCORE). Approximate cost of each group of patients was estimated by the average number of days in the Intensive Care Unit and days in the postoperative ward multiplied by the respective daily costs as determined by the Ministry of Health. We then added the fixed cost of the components used in the operating room (manpower and disposables). The final estimated cost (the outcome variable) was then evaluated as it relates to type of surgery and clinical profile. ANOVA was used to analyze cost variability between groups, and backward regression analysis to determine the respective effect of the abovementioned variables on cost. Because of non-normal distribution, both costs and lengths of stay were Log-transformed. RESULTS: Altogether there were 5496 patients: 3863, 836, 685 and 112 in the isolated CABG, CABG + valve, 1 valve and 2 valves replacement groups. By ANOVA, the costs in all EuroSCORE subgroups were significantly different from each other, increasing with increased EuroSCORE subgroup. Cost was also significantly different among procedure groups, increasing from simple CABG to single valve surgery to CABG + valve surgery to 2-valve surgery. In backward stepwise multiple regression analysis, both type of procedure and EuroSCORE group significantly impacted cost. ICU stay and Ward stay were significantly but weakly related while EuroSCORE subgroup was highly predictive of both ICU stay and ward stay. CONCLUSIONS: The cost of performing heart surgery today is directly influenced by both patient profile as well as type of surgery, both of which can be quantified. Modern day technology is costly yet has become mandatory. Thus reimbursement for heart surgery should be based on differential criteria, namely clinical risk profile as well as type of surgery. Our results suggest an urgent need for design and implementation of a differential tariff model in the Israeli reimbursement system. We suggest that a model using a fixed, average price according to the type of procedure costs, in addition to a variable hospitalization cost (ICU + ward) determined by the patient EuroSCORE or EuroSCORE subgroup should enable an equitable reimbursement to hospitals, based on their case mix.

Effects of commercial metronidazole and metronidazole benzoate suspensions on food intake in chinchillas.

OBJECTIVES: To evaluate if commercially available metronidazole and metronidazole benzoate suspensions cause a reduction in food intake in healthy chinchillas and if the reduction in food intake is dose-dependent. MATERIALS AND METHODS: Twelve chinchillas were used in a randomised, controlled, blinded, complete-crossover study. All treatments were administered orally every 12 hours for 3 days. Metronidazole (125 mg/mL) was administered at 20 mg/kg and metronidazole benzoate (25 mg/mL) was administered at 20 and 10 mg/kg. Food intake was recorded daily. The washout period between treatments was at least 14 days. RESULTS: At 20 mg/kg PO q12h administration of both commercial suspensions resulted in a significant reduction of food intake. The greatest mean reduction in food intake occurred after 2 to 3 days of drug administration (metronidazole: -54 ± 25%; metronidazole benzoate: -44 ± 36%). After administration of metronidazole benzoate at 10 mg/kg PO q12h, the reduction in food intake was significantly less pronounced (-24 ± 36%), suggesting that negative effect of metronidazole on food intake in chinchillas is dose-dependent. Variation in metronidazole-induced food intake reduction differed widely between individual chinchillas. CLINICAL SIGNIFICANCE: The oral administration of commercial metronidazole and metronidazole benzoate suspensions results in a dose-dependent clinically relevant reduction in food intake in chinchillas. Metronidazole should be used cautiously in this species and food intake should be monitored during treatment. Future studies are needed in order to determine if metronidazole at 10 mg/kg q12h is an effective therapeutic dosage in chinchillas.

Development and internal validation of a diagnostic prediction model for COVID-19 at time of admission to hospital.

BACKGROUND: Early coronavirus disease 2019 (COVID-19) diagnosis prior to laboratory testing results is crucial for infection control in hospitals. Models exist predicting COVID-19 diagnosis, but significant concerns exist regarding methodology and generalizability. AIM: To generate the first COVID-19 diagnosis risk score for use at the time of hospital admission using the TRIPOD (transparent reporting of a multivariable prediction model for individual prognosis or diagnosis) checklist. DESIGN: A multivariable diagnostic prediction model for COVID-19 using the TRIPOD checklist applied to a large single-centre retrospective observational study of patients with suspected COVID-19. METHODS: 581 individuals were admitted with suspected COVID-19; the majority had laboratory-confirmed COVID-19 (420/581, 72.2%). Retrospective collection was performed of electronic clinical records and pathology data. RESULTS: The final multivariable model demonstrated AUC 0.8535 (95% confidence interval 0.8121-0.8950). The final model used six clinical variables that are routinely available in most low and high-resource settings. Using a cut-off of 2, the derived risk score has a sensitivity of 78.1% and specificity of 86.8%. At COVID-19 prevalence of 10% the model has a negative predictive value (NPV) of 96.5%. CONCLUSIONS: Our risk score is intended for diagnosis of COVID-19 in individuals admitted to hospital with suspected COVID-19. The score is the first developed for COVID-19 diagnosis using the TRIPOD checklist. It may be effective as a tool to rule out COVID-19 and function at different pandemic phases of variable COVID-19 prevalence. The simple score could be used by any healthcare worker to support hospital infection control prior to laboratory testing results.

Engineering of impact ionization characteristics in In0.53Ga0.47As/Al0.48In0.52As superlattice avalanche photodiodes on InP substrate.

We report on engineering impact ionization characteristics of In0.53Ga0.47As/Al0.48In0.52As superlattice avalanche photodiodes (InGaAs/AlInAs SL APDs) on InP substrate to design and demonstrate an APD with low k-value. We design InGaAs/AlInAs SL APDs with three different SL periods (4 ML, 6 ML, and 8 ML) to achieve the same composition as Al0.4Ga0.07In0.53As quaternary random alloy (RA). The simulated results of an RA and the three SLs predict that the SLs have lower k-values than the RA because the electrons can readily reach their threshold energy for impact ionization while the holes experience the multiple valence minibands scattering. The shorter period of SL shows the lower k-value. To support the theoretical prediction, the designed 6 ML and 8 ML SLs are experimentally demonstrated. The 8 ML SL shows k-value of 0.22, which is lower than the k-value of the RA. The 6 ML SL exhibits even lower k-value than the 8 ML SL, indicating that the shorter period of the SL, the lower k-value as predicted. This work is a theoretical modeling and experimental demonstration of engineering avalanche characteristics in InGaAs/AlInAs SLs and would assist one to design the SLs with improved performance for various SWIR APD application.

Million-year lag times in a post-orogenic sediment conveyor.

Understanding how sediment transport and storage will delay, attenuate, and even erase the erosional signal of tectonic and climatic forcings has bearing on our ability to read and interpret the geologic record effectively. Here, we estimate sediment transit times in Australia's largest river system, the Murray-Darling basin, by measuring downstream changes in cosmogenic 26Al/10Be/14C ratios in modern river sediment. Results show that the sediments have experienced multiple episodes of burial and reexposure, with cumulative lag times exceeding 1 Ma in the downstream reaches of the Murray and Darling rivers. Combined with low sediment supply rates and old sediment blanketing the landscape, we posit that sediment recycling in the Murray-Darling is an important and ongoing process that will substantially delay and alter signals of external environmental forcing transmitted from the sediment's hinterland.

Comparing abundance distributions and range maps in spatial conservation planning for migratory species.

Most spatial conservation planning for wide-ranging or migratory species is constrained by poor knowledge of species' spatiotemporal dynamics and is only based on static species' ranges. However, species have substantial variation in abundance across their range and migratory species have important spatiotemporal population dynamics. With growing ecological data and advancing analytics, both of these can be estimated and incorporated into spatial conservation planning. However, there is limited information on the degree to which including this information affects conservation planning. We compared the performance of systematic conservation prioritizations for different scenarios based on varying the input species' distributions by ecological metric (abundance distributions versus range maps) and temporal sampling resolution (weekly, monthly, or quarterly). We used the example of a community of 41 species of migratory shorebirds that breed in North America, and we used eBird data to produce weekly estimates of species' abundances and ranges. Abundance distributions at a monthly or weekly resolution led to prioritizations that most efficiently protected species throughout the full annual cycle. Conversely, spatial prioritizations based on species' ranges required more sites and left most species insufficiently protected for at least part of their annual cycle. Prioritizations with only quarterly species ranges were very inefficient as they needed to target 40% of species' ranges to include 10% of populations. We highlight the high value of abundance information for spatial conservation planning, which leads to more efficient and effective spatial prioritization for conservation. Overall, we provide evidence that spatial conservation planning for wide-ranging migratory species is most robust and efficient when informed by species' abundance information from the full annual cycle.

PD-L1 receptor expression in vulvar carcinomas is HPV-independent.

PD-L1 (programmed cell death 1 ligand) is expressed on many cancer cells and prevents tumor cell death by blocking T cell activity. PD-L1 overexpression has been reported in squamous cell carcinomas of head and neck and lung cancer. To better understand the role of PD-L1 expression in vulvar cancer, we analyzed PD-L1 expression by immunohistochemistry in 55 well-characterized squamous cell carcinomas of vulva. PD-L1 was found in 72.7% of tumors. 27.3% of vulvar carcinomas showed moderate or strong PD-L1 expression. PD-L1 expression was correlated with low tumor stage (p < 0.05). There was no association to other clinicopathological parameters, HPV status, and overall survival of vulvar carcinoma patients. In conclusion, PD-L1 overexpression is detectable in a substantial proportion of vulvar carcinomas in all stages independent of HPV and may be a suitable therapeutic target in these cancers.

Rotational Energy as Mass in H_{3}

We have made precise measurements of the cyclotron frequency ratios H_{3}^{+}/HD^{+} and H_{3}^{+}/^{3}He^{+} and observe that different H_{3}^{+} ions result in different cyclotron frequency ratios. We interpret these differences as due to the molecular rotational energy of H_{3}^{+} changing its inertial mass. We also confirm that certain high J, K rotational levels of H_{3}^{+} have mean lifetimes exceeding several weeks. From measurements with the lightest H_{3}^{+} ion we obtain lower limits on the atomic masses of deuterium and helium-3 with respect to the proton.

Correction to: The use of PIPAC (pressurized intraperitoneal aerosol chemotherapy) in gynecological oncology: a statement by the Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) Kommission Ovar, AGO Study Group, North-Eastern German Society of Gynaecologic Oncology (NOGGO), AGO Austria and AGO Switzerland.

The title of the article has been published incorrectly. The correct title is given below.

The use of PIPAC (pressurized intraperitoneal aerosol chemotherapy) in gynecological oncology: a statement by the "Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR)", the Swiss and Austrian AGO, and the North-Eastern German Society of Gynaecologic Oncology.

BACKGROUND: Ovarian, tubal, and peritoneal carcinomas primarily affect the peritoneal cavity, and they are typically diagnosed at an advanced tumor stage (Foley, Rauh-Hain, del Carmen in Oncology (Williston Park) 27:288-294, 2013). In the course of primary surgery, postoperative tumor residuals are, apart from the tumor stage, the strongest independent factors of prognosis (du Bois, Reuss, Pujade-Lauraine, Harter, Ray-Coquard, Pfisterer in Cancer 115:1234-1244, 2009). Due to improved surgical techniques, including the use of multi-visceral procedures, macroscopic tumor clearance can be achieved in oncological centers, in most cases (Harter, Muallem, Buhrmann et al in Gynecol Oncol 121:615-619, 2011). However, to date, it has not been shown that peritoneal carcinomatosis is, per se, an independent factor of prognosis or that it excludes the achievement of tumor clearance. Several studies have shown that a preceding drug therapy in peritoneal carcinomatosis could positively influence the overall prognosis (Trimbos, Trimbos, Vergote et al in J Natl Cancer Inst 95:105-112, 2003). In relapses of ovarian carcinoma, studies have shown that peritoneal carcinomatosis is a negative predictor of complete tumor resection; however, when it is possible to resect the tumor completely, peritoneal carcinomatosis does not play a role in the prognosis (Harter, Hahmann, Lueck et al in Ann Surg Oncol 16:1324-1330, 2009). RESULTS: PIPAC is a highly experimental method for treating patients with ovarian, tubal, and peritoneal cancer. To date, only three studies have investigated a total of 184 patients with peritoneal carcinomatosis (Grass, Vuagniaux, Teixeira-Farinha, Lehmann, Demartines, Hubner in Br J Surg 104:669-678, 2017). Only some of those studies were phase I/II studies that included PIPAC for patients with different indications and different cancer entities. It is important to keep in mind that the PIPAC approach is associated with relatively high toxicity. To date, no systematic dose-finding studies have been reported. Moreover, no studies have reported improvements in progression-free or overall survival associated with PIPAC therapy. CONCLUSIONS: Randomized phase III studies are required to evaluate the effect of this therapy compared to other standard treatments (sequential or simultaneous applications with systemic chemotherapy). In cases of ovarian, tubal, and peritoneal cancer, PIPAC should not be performed outside the framework of prospective, controlled studies.

Gota úrica visceral em bobo-pequeno (Puffinus puffinus) no sul do Brasil / Visceral gout uric in manx shearwater (Puffinus puffinus) in Southern of Brazil

A gota úrica visceral é uma doença que acomete répteis, aves e mamíferos. Caracteriza-se por depósitos de cristais de urato e ácido úrico em diferentes órgãos da região visceral. O objetivo deste trabalho foi relatar um caso de gota úrica visceral em um indivíduo de bobo-pequeno (Puffinus puffinus) encontrado morto no litoral norte de Santa Catarina, sul do Brasil. No período de 20 de agosto de 2015 a 20 de abril de 2016, as praias dos municípios de Araquari, Barra do Sul, São Francisco do Sul e Itapoá foram monitoradas diariamente para o registro e a recuperação de tetrápodes marinhos mortos, incluindo aves marinhas. Foram encontrados e necropsiados 84 indivíduos. Um deles apresentou o pericárdio aderido ao miocárdio e com a coloração esbranquiçada. Os rins, o fígado e os pulmões continham inúmeros pontos esbranquiçados. A ocorrência dessa patologia na espécie foi de 1,19%. Trata-se do primeiro relato de bobo-pequeno com gota úrica visceral encontrado no Brasil.(AU)

Visceral gout uric is a disease that affects reptiles, birds and mammals. It is characterized by urate crystal deposits and uric acid in different organs of visceral region. The objective of this study was to report a case of visceral urica drop in a manx shearwater individual (Puffinus puffinus) found dead on the north coast of Santa Catarina, Southern Brazil. In the period from 20 August 2015 and 20 April 2016, beaches in the municipalities of Araquari, Barra do Sul, São Francisco do Sul and Itapoá, were monitored daily for the registration and recovery of dead marine tetrapods, including seabirds. Eighty-four were found and necropsied. One of them was whitish in color and had the pericardium adhered to the myocardium. The kidneys, liver and lungs contained numerous whitish dots. The occurrence of this disease in the species was 1.19%. This is the first manx shearwater report with visceral urica drop found in Brazil.(AU)

Systematic review of the efficacy and safety of biological therapy for inflammatory conditions in HIV-infected individuals.

Biologic therapies are injectable immunomodulatory agents directed against specific immune cell or chemical targets. They have transformed the lives of HIV-uninfected individuals with severe inflammatory conditions including psoriasis, rheumatoid arthritis, and ulcerative colitis. The perceived increased infection risk associated with these agents means that HIV-infected individuals have not been included in randomised control trials of these drugs. The literature for use of biologic therapies in HIV-infected populations is limited to case reports and case series. There are additional data on use of rituximab, a monoclonal antibody against B lymphocytes, in the setting of HIV-associated haematological malignancy. We performed a systematic review of efficacy and safety of biologic therapy for inflammatory conditions in HIV-infected individuals. Our systematic review identified 37 treatment episodes with six different biologic agents encompassing 10 different inflammatory conditions. Broadly, efficacy of the agents studied was comparable to reports from HIV-uninfected patients. Both infectious and non-infectious sequelae were also comparable with trial data from HIV-uninfected patients. HIV control, even for the minority of individuals not receiving anti-retroviral therapy (ART) at the time of biologic therapy, was not adversely affected. However, detail was limited concerning ART regimens and both immunological and virological parameters of follow-up. Overall available literature is of very low quality and likely subject to publication bias of successful cases. Firm conclusions are not possible regarding the efficacy and safety of biologic agents in HIV-infected individuals; however, there appear to be sufficient data to warrant inclusion of individuals with well-controlled HIV in future trial studies.

Comparison of quartz vials with polypropylene vials for rapid cryopreservation of human ovarian tissue.

BACKGROUND: Because higher survival of follicles during the freezing/thawing procedure improves the quality of cryopreserved tissue reimplanted after oncological therapies, defining an optimal method for human ovarian tissue cryopreservation remains a major issue in this field. One option to improve the cryopreservation procedure is to use better materials, i.e., vials with better conductivity. The aim of this study was to compare polypropylene (PP) with quartz vials. Between September 2012 and January 2013, eight patients were recruited. The ovarian cortex was cut into 3 slices, assigned randomly to a fresh and a cryopreserved group in PP (method B) or quartz vials (method C). Histological and immunohistochemical (IHC) analysis were used. For IHC three antibodies were analyzed: Ki67 (proliferation index), Bcl2 (anti apoptotic index) and Hsp70 (stress index). RESULTS: The majority of GCs showed positive staining for Bcl2 in both cryopreservation device, with higher expression in group C than in group B. Oocytes and their nuclei showed intense positive staining for ki67 in both methods B and C, and also a patch positive stromal cells staining for Ki67. Expression of hsp70 was not increased after cryopreservation. CONCLUSIONS: Cryopreservation using quartz vials led to larger numbers of good follicles while maintaining consistent preservation for stromal cells and vessels.

Determination of discharge parameters via OES at the Linac4 H⁻ ion source.

Optical emission spectroscopy (OES) measurements of the atomic Balmer series and the molecular Fulcher transition have been carried out at the Linac4 ion source in order to determine plasma parameters. As the spectroscopic system was only relatively calibrated, the data evaluation only yielded rough estimates of the plasma parameters (T(e) ≈ 1.2 eV, n(e) ≈ 1 × 10(19) m(-3), and n(H/)n(H2) ≈ 0.5 at standard operational parameters). The analysis of the Fulcher transition revealed a non-thermal "hockey-stick" rotational population of the hydrogen molecules. At varying RF power, the measurements at the on-axis line of sight (LOS) showed a peak in the rotational temperatures between 25 and 40 kW of RF power, whereas a steady decrease with power was observed at a tilted LOS, indicating the presence of strong plasma parameter gradients.

Linac4 H⁻ ion sources.

CERN's 160 MeV H(-) linear accelerator (Linac4) is a key constituent of the injector chain upgrade of the Large Hadron Collider that is being installed and commissioned. A cesiated surface ion source prototype is being tested and has delivered a beam intensity of 45 mA within an emittance of 0.3 π ⋅ mm ⋅ mrad. The optimum ratio of the co-extracted electron- to ion-current is below 1 and the best production efficiency, defined as the ratio of the beam current to the 2 MHz RF-power transmitted to the plasma, reached 1.1 mA/kW. The H(-) source prototype and the first tests of the new ion source optics, electron-dump, and front end developed to minimize the beam emittance are presented. A temperature regulated magnetron H(-) source developed by the Brookhaven National Laboratory was built at CERN. The first tests of the magnetron operated at 0.8 Hz repetition rate are described.

Statement of the AGO Kommission Ovar, AGO Study Group, NOGGO, AGO Austria and AGO Switzerland Regarding the Use of Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Ovarian Cancer.

The AGO Kommission Ovar already published a statement in 2013, warning about the uncritical use of hyperthermic intraperitoneal chemotherapy (HIPEC) outside controlled studies. This statement has now been updated after the most recent literature was reviewed by AGO Kommission Ovar, the AGO Study Group, NOGGO, AGO Austria and AGO Switzerland. The authors conclude that HIPEC remains experimental. Its use is not recommended and should be rejected outside of prospective controlled trials.

Isotopically exchangeable Al in coastal lowland acid sulfate soils.

Periodic discharges of high concentrations of aluminium (Al) causing fish kills and other adverse effects occur worldwide in waterways affected by coastal lowland acid sulfate soils (CLASS). The exchangeability - a metal's ability to readily transfer between the soil solid- and solution-phases - of Al in these soils is therefore of particular importance as it has implications for metal transport, plant availability and toxicity to living organisms. In the present study, the concentrations of isotopically exchangeable Al (E values) were measured in 27 CLASS and compared with common salt extractions (i.e. KCl and CuCl2) used to estimate exchangeable soil pools of Al. E values of Al were high in the soils, ranging from 357 to 3040 mg·kg(-1). Exchangeable concentrations estimated using 1 M KCl were consistently lower than measured E values, although a reasonable correlation was obtained between the two values (E=1.68×AlKCl, r(2)=0.66, n=25). The addition of a 0.2 M CuCl2 extraction step improved the 1:1 agreement between extractable and isotopically exchangeable Al concentrations, but lead to significant mobilisation of non-isotopically exchangeable Al in surficial 'organic-rich' CLASS having E values<1000 mg·kg(-1). It was concluded that currently used (i.e. 1 M KCl) methodology severely underestimates exchangeable Al and total actual acidity values in CLASS and should be corrected by a factor similar to the one determined here.

Blood culture fluorescence rates predict severity and mortality of invasive pneumococcal pneumonia.

Invasive pneumococcal pneumonia is associated with high rates of mortality. Clinical assessment tools have poor sensitivity for predicting clinical outcomes. Molecular measurements of bacterial load correlate closely with clinical outcome but require specialist facilities and expertise. This study describes how routine blood culture testing can estimate bacterial load and predict clinical outcome for invasive pneumococcal pneumonia. Between December 2009 to March 2014, clinical and laboratory data were collected for 50 patients with Streptococcus pneumoniae bacteraemia secondary to community-acquired pneumonia. Fluorescence rates (FR) were calculated from growth curves generated by BACTEC blood culture analysers by dividing change in fluorescence units (FU), measured at the first point of detectable fluorescence and at the point of automated BACTEC positivity, by time in hours. The mean age of the patients was 70.6 years (49.6-86.3). Forty patients survived invasive pneumococcal disease and ten patients died. These two groups did not significantly differ by demographic or clinical characteristics. The mean FR for the non-survival group (3.62 × 10(-3) FU/h) was significantly higher (p < 0.001) than that of the survival group (1.73 × 10(-3) FU/h). FR did not vary by serotype. We determined that an FR of 2.59 × 10(-3) FU/h might represent a useful threshold for predicting high mortality risk with a sensitivity of 91 % and a specificity of 97 %. Our FR calculation uses cheap and accessible routine blood culture techniques to predict mortality in a small retrospective cohort study. In patients admitted to hospital with pneumococcal bacteraemia and, potentially, other organisms, this single tool could guide early escalation of clinical care.

Assessment and refinement of intra-bone marrow transplantation in mice.

Intra-bone marrow transplantation (IBMT) may improve the seeding efficiency of transplanted hematopoietic stem cells compared to the routinely used intravenous injection. Current IBMT protocols are optimized for ease of use and to improve experimental results. However, there have been no investigations to assess the impact of IBMT on animal welfare. Here, we report the results of pain assessment after IBMT and the effects of refinements to the current standard procedure. IBMT was performed in either the tibia or the femur of a recipient mouse under general anesthesia. Impact was determined using clinical scoring of different parameters (lameness, grip capacity, body weight loss, footprint analysis), behavioural tests (burrowing, open-field), monitoring of stress hormones and post-mortem histology. The results revealed that IBMT definitely induces severe post-operative distress. Although IBMT in the tibia is technically easier, the degree of impairment and the distress observed were consistently higher than for transplantation in the femur. A refinement for IBMT in the tibia was achieved by using 30- instead of 26-gauge needles and by sparing the patellar tendon. Consequently, for IBMT, we recommend either using the femur, or if the tibia is required due to its better feasibility, using our refined protocol. Furthermore, IBMT should definitely be limited to one leg per animal.