A resonant sextuplet of sub-Neptunes transiting the bright star HD 110067.

Planets with radii between that of the Earth and Neptune (hereafter referred to as 'sub-Neptunes') are found in close-in orbits around more than half of all Sun-like stars1,2. However, their composition, formation and evolution remain poorly understood3. The study of multiplanetary systems offers an opportunity to investigate the outcomes of planet formation and evolution while controlling for initial conditions and environment. Those in resonance (with their orbital periods related by a ratio of small integers) are particularly valuable because they imply a system architecture practically unchanged since its birth. Here we present the observations of six transiting planets around the bright nearby star HD 110067. We find that the planets follow a chain of resonant orbits. A dynamical study of the innermost planet triplet allowed the prediction and later confirmation of the orbits of the rest of the planets in the system. The six planets are found to be sub-Neptunes with radii ranging from 1.94R⊕ to 2.85R⊕. Three of the planets have measured masses, yielding low bulk densities that suggest the presence of large hydrogen-dominated atmospheres.

Tourniquet and closed-suction drains in total knee arthroplasty. No beneficial effects on bleeding management and knee function at a higher cost.

BACKGROUND: Blood loss is a major concern in total knee arthroplasty (TKA) along with postoperative knee function. The present study explores the impact of tourniquet (T) and closed-suction drains (D) on these parameters in TKA. MATERIALS AND METHODS: A prospective study was conducted on 111 patients admitted for TKA. Subjects were divided into three groups: 36 in group T+D+, 42 in T-D+ and 33 in T-D- (where T+: prolonged tourniquet use, T-: cementation-only tourniquet, D+: closed-suction drain use, and D-: no drain). RESULTS: No statistically significant differences were observed among the three groups(T+D+, T-D+ and T-D-) for total blood loss, hemoglobin levels over the first six postoperative weeks and blood transfusion rate. Intraoperative bleeding was significantly reduced in T+ subjects compared to T- subjects (100±88mL vs. 279±235mL respectively, P<0.001), yet length of surgery was unaffected. Hidden blood loss was lower in D+ subjects compared to D- subjects (1161±554mL vs. 1667±554mL respectively, P<0.001), but was offset by the blood loss in the drains. Early postoperative range of motion (ROM) was superior in group T-D- compared to group T+D+. Nevertheless, postoperative week 6 ROM was similar between the 3 groups as was patient-reported postoperative pain. A patient with a drain represents 35min of extra nursing time and a total cost of $31.87 CAD. CONCLUSIONS: Whole-course tourniquet and closed-suction drain use in TKA do not yield beneficial results while increasing costs. Their use is therefore deemed unnecessary. LEVEL OF EVIDENCE: III (case control prospective study).

The impact of a standardized order set for the management of non-hip fragility fractures in a Fracture Liaison Service.

We analysed the impact of a standardized order set empowering staff nurses to independently manage a Fracture Liaison Service over a 9-month period. Nurses identified between 30 and 70 % of non-hip fragility fractures to the unit in charge of management over time. The latter managed 58 % of referred patients. INTRODUCTION: The main goal of this study was to evaluate the impact of a standardized order set empowering nurses to independently manage a fracture liaison service (FLS). METHODS: Since November 2014, an order set allowed nurses of a Montreal hospital, Quebec, Canada to entirely manage an FLS on their own. Nurses followed an 6-h training program on-site. Emergency department (ED) and orthopaedic outpatient clinic (OC) nurses identified non-hip fragility fractures. Medical day treatment unit (MDTU) nurses were in charge of the management (investigation and treatment initiation). The list of patients, 50 years and older, with a fracture were retrieved for the period of November 2014 to July 2015. Performance was assessed with the rate of identification over time and the rate of management of non-hip fragility fractures. RESULTS: Over the 9-month period, 346 patients of ≥50 years old were seen for a fracture, of which 190 met fragility criteria (excluding hip fractures). A sinusoid pattern of rates of identification between 30-70 % was observed over time. An average proportion of 58.1 % of fracture patients were managed by MDTU nurses. CONCLUSIONS: A standardized order set legally allowing nurses to manage an FLS led to identification rates varying from 30-70 % and a management rate close to 60 % for referred patients over a 9-month period, which largely exceeds that of standard care. Identification was mostly compromised by difficulty integrating the order set into routine practice. Enforcement of the hospital policy on fragility fractures could help yield efficiency of identification of osteoporosis-related fractures by the staff.

Spatiotemporal Co-occurrence of Flanders and West Nile Viruses Within Culex Populations in Shelby County, Tennessee.

West Nile virus (WNV) and Flanders virus (FLAV) can cocirculate in Culex mosquitoes in parts of North America. A large dataset of mosquito pools tested for WNV and FLAV was queried to understand the spatiotemporal relationship between these two viruses in Shelby County, TN. We found strong evidence of global clustering (i.e., spatial autocorrelation) and overlapping of local clustering (i.e., Hot Spots based on Getis Ord Gi*) of maximum likelihood estimates (MLE) of infection rates (IR) during 2008-2013. Temporally, FLAV emerges and peaks on average 10.2 wk prior to WNV based on IR. Higher levels of WNV IR were detected within 3,000 m of FLAV-positive pool buffers than outside these buffers.

Proteogenomic-based discovery of minor histocompatibility antigens with suitable features for immunotherapy of hematologic cancers.

Pre-clinical studies have shown that injection of allogeneic T cells primed against a single minor histocompatibility antigen (MiHA) could cure hematologic cancers (HC) without causing any toxicity to the host. However, translation of this approach in humans has been hampered by the paucity of molecularly defined human MiHAs. Using a novel proteogenomic approach, we have analyzed cells from 13 volunteers and discovered a vast repertoire of MiHAs presented by the most common HLA haplotype in European Americans: HLA-A*02:01;B*44:03. Notably, out of >6000 MiHAs, we have identified a set of 39 MiHAs that share optimal features for immunotherapy of HCs. These 'optimal MiHAs' are coded by common alleles of genes that are preferentially expressed in hematopoietic cells. Bioinformatic modeling based on MiHA allelic frequencies showed that the 39 optimal MiHAs would enable MiHA-targeted immunotherapy of practically all HLA-A*02:01;B*44:03 patients. Further extension of this strategy to a few additional HLA haplotypes would allow treatment of almost all patients.

Agreement between physicians' and nurses' clinical decisions for the management of the fracture liaison service (4iFLS): the Lucky Bone™ program.

UNLABELLED: We determined if nurses can manage osteoporotic fractures in a fracture liaison service by asking a rheumatologist and an internist to assess their clinical decisions. Experts agreed on more than 94 % of all nurses' actions for 525 fragility fracture patients, showing that their management is efficient and safe. INTRODUCTION: A major care gap exists in the investigation of bone fragility and initiation of treatment for individuals who have sustained a fragility fracture. The implementation of a fracture liaison service (FLS) managed by nurses could be the key in resolving this problem. The aim of this project was to obtain agreement between physicians' and nurses' clinical decisions and evaluate if the algorithm of care is efficient and reliable for the management of a FLS. METHODS: Clinical decisions of nurses for 525 subjects in a fracture liaison service between 2010 and 2013 were assessed by two independent physicians with expertise in osteoporosis treatment. RESULTS: Nurses succeeded in identifying all patients at risk and needed to refer 27 % of patients to an MD. Thereby, they managed autonomously 73 % of fragility fracture patients. No needless referrals were made according to assessing physicians. Agreement between each evaluator and nurses was of >97 %. Physicians' decisions were the same in >96 %, and Gwet AC11 coefficient was of >0.960 (almost perfect level of agreement). All major comorbidities were adequately managed. CONCLUSIONS: High agreement between nurses' and physicians' clinical decisions indicate that the independent management by nurses of a fracture liaison service is safe and should strongly be recommended in the care of patients with a fragility fracture. This kind of intervention could help resolve the existing care gap in bone fragility care as well as the societal economic burden associated with prevention and treatment of fragility fractures.

Favorable long-term outcome of patients with multiple myeloma using a frontline tandem approach with autologous and non-myeloablative allogeneic transplantation.

Despite survival improvement with novel agents and use of autologous hematopoietic stem cell transplantation (HSCT), cure of patients with multiple myeloma (MM) remains anecdotal. Initial observations suggested that chronic GvHD was accompanied by an anti-myeloma effect after myeloablative HSCT, but unfortunately this procedure was hampered by high non-relapse mortality (NRM). To maximize the anti-myeloma effect and minimize NRM, we developed a non-myeloablative (NMA) regimen associated with a high incidence of chronic GvHD and tested its efficacy on patient survival and disease eradication. From 2001 to 2010, 92 patients aged ⩽ 65 years with a compatible sibling donor received autologous HSCT followed by an outpatient NMA allogeneic HSCT using a conditioning of fludarabine and cyclophosphamide. Patient median age was 52 years and 97% presented Durie-Salmon stages II-III disease. After a median follow-up of 8.8 years, probability of 10-year progression free and overall survival were 41% and 62%, respectively. Although the cumulative incidence of extensive chronic GvHD was high (at 79%), the majority of long-term survivors were off immunosuppressive drugs by year 5 and NRM was low (at 10%). Together, our results suggest that potential MM cure can be achieved with NMA transplantation regimens that maximize graft-versus-myeloma effect and minimize NRM.

Evaluation of various types of supplemental food for two species of predatory mites, Amblyseius swirskii and Neoseiulus cucumeris (Acari: Phytoseiidae).

Although phytoseiids are best known as predators of phytophagous mites and other small arthropods, several species can also feed and reproduce on pollen. In laboratory assays, we assessed the profitability of two types of dietary supplements (three pollen species-cattail, maize and apple-and eggs of the Mediterranean flour moth, Ephestia kuehniella) for the two species of predatory mites most commonly used as biocontrol agents in horticulture in Canada, Neoseiulus cucumeris and Amblyseius swirskii. We measured the effects of each diet on phytoseiid fitness parameters (survival, development, sex ratio, fecundity) and, as a means of comparison, when fed larvae of the common targeted pest species, western flower thrips Frankliniella occidentalis. A soluble protein assay was also performed on the alternative food sources as protein content is often linked to high nutritive value according to the literature. All food sources tested were suitable for N. cucumeris and A. swirskii, both species being able to develop from egg to adult. The dietary supplements had a beneficial impact on biological parameters, mostly resulting in shorter development times and higher survival rates when compared to thrips larvae. Amblyseius swirskii exhibited a wider dietary range than N. cucumeris. Overall, flour moth eggs, cattail pollen and apple pollen are food sources of equal quality for A. swirskii, whereas apple and cattail pollen are better when it comes to N. cucumeris. In contrast, maize pollen is a less suitable food source for N. cucumeris and A. swirskii. Soluble protein content results did not match the prediction under which the most beneficial food source would contain the highest concentration in protein.

Apple pollen as a supplemental food source for the control of western flower thrips by two predatory mites, Amblyseius swirskii and Neoseiulus cucumeris (Acari: Phytoseiidae), on potted chrysanthemum.

It has been shown that pollen as a dietary supplement may increase the establishment (development and reproduction) and survival of phytoseiid predatory mites, and therefore the pest control these mites can provide. In this study, the role of apple pollen as a supplemental food source was assessed as a means to increase the efficiency of two predatory mite species, Neoseiulus cucumeris and Amblyseius swirskii, for control of western flower thrips, Frankliniella occidentalis, under greenhouse conditions. The impact of apple pollen on thrips populations and predator establishment on a greenhouse chrysanthemum crop was determined over a 4-week period. The two mite species were released separately and in combination with and without pollen with two control treatments (thrips only and thrips + pollen). The introduction of A. swirskii together with pollen application provided the best control of thrips (adults and immatures). The establishment of N. cucumeris was very low in the crop during the greenhouse trial. This could be attributable, in part, to their response to extreme temperature ranges that were encountered during the greenhouse cage trials. The use of A. swirskii alone and the mixed population of the two predatory mite species without pollen resulted in the lowest frequencies of plants with heavy damage, followed by the same treatments with the addition of apple pollen.

The TGF-ß-Smad3 pathway inhibits CD28-dependent cell growth and proliferation of CD4 T cells.

Transforming growth factor-ß (TGF-ß) maintains self-tolerance through a constitutive inhibitory effect on T-cell reactivity. In most physiological situations, the tolerogenic effects of TGF-ß depend on the canonical signaling molecule Smad3. To characterize how TGF-ß/Smad3 signaling contributes to maintenance of T-cell tolerance, we characterized the transcriptional landscape downstream of TGF-ß/Smad3 signaling in resting or activated CD4 T cells. We report that in the presence of TGF-ß, Smad3 modulates the expression of >400 transcripts. Notably, we identified 40 transcripts whose expression showed Smad3 dependence in both resting and activated cells. This 'signature' confirmed the non-redundant role of Smad3 in TGF-ß biology and identified both known and putative immunoregulatory genes. Moreover, we provide genomic and functional evidence that the TGF-ß/Smad3 pathway regulates T-cell activation and metabolism. In particular, we show that TGF-ß/Smad3 signaling dampens the effect of CD28 stimulation on T-cell growth and proliferation. The impact of TGF-ß/Smad3 signals on T-cell activation was similar to that of the mTOR inhibitor Rapamycin. Considering the importance of co-stimulation on the outcome of T-cell activation, we propose that TGF-ß-Smad3 signaling may maintain T-cell tolerance by suppressing co-stimulation-dependent mobilization of anabolic pathways.

Lateral compression fractures of the superior pubic ramus with intra-articular extension.

A total of 30 patients with lateral compression fractures of the pelvis with intra-articular extension into the anterior column were followed for a mean of 4.2 years (2 to 6), using the validated functional outcome tools of the musculoskeletal function assessment and the short-form health survey (SF-36). The functional outcome was compared with that of a series of patients who had sustained type-B1 and type-C pelvic fractures. The lateral-compression group included 20 men and ten women with a mean age of 42.7 years (13 to 84) at the time of injury. Functional deficits were noted for the mental component summary score (p = 0.008) and in the social function domain (p < 0.05) of the SF-36. There was no evidence of degenerative arthritis in the lateral-compression group. However, they had high functional morbidity including greater emotional and psychological distress.

Proximal humerus fractures treated by percutaneous locking plate internal fixation.

INTRODUCTION: There is no consensually accepted recommendation for optimum surgical treatment of unstable fractures of the proximal humerus. HYPOTHESIS: Locked and minimally-invasive plating is a promising treatment option. MATERIALS AND METHODS: The aim of this prospective, multicentric study is to describe a recently introduced surgical technique for proximal humeral fractures and to evaluate the radiographic and clinical outcomes of this operation. Closed and minimally-invasive reduction is first performed. A proximal humerus specific locking plate featuring multiple-angle screws is secondly implanted. Proper identification and protection of the axillary nerve with the index finger during plate insertion on the lateral humeral side is highly advisable. If it can't be palpated, a classic delto-pectoral approach should be preferred. Thirty-four patients were included in this study with a 1-year minimal postoperative follow-up. Twenty-two patients presented a two-part surgical neck fracture according to the Neer classification and 12 patients had a three-part valgus-impacted fracture. DASH (Disabilities of the Arm, Shoulder and Hand) and Constant scoring systems were used for functional evaluation. RESULTS: Specifically, no axillary nerve injury and no loss of reduction were observed. The median Constant score and the mean DASH score were 82 and 26 respectively at 1-year follow-up. The age-adjusted functional scores values were satisfactory. Two of the patients (6%) required surgical revision for intra-articular screw penetration. DISCUSSION: Our study suggests that percutaneous plating with angular screw fixation of proximal humeral fractures is a safe and effective method, which produces good functional and radiologic outcomes. These minimally-invasive techniques allowing a better preservation of soft-tissues help promote early functional recovery. This more friendly approach combined to upgraded implants and instruments will also improve early and long-term outcomes of these fractures.

Long-term outcome of surgically-treated habitual patellar dislocation in children with coexistent patella alta. Minimum follow-up of 11 years.

We retrospectively reviewed the operative treatment carried out between 1988 and 1994 of eight patients with habitual patellar dislocation. In four the condition was bilateral. All patients had recurrent dislocation with severe functional disability. The surgical technique involved distal advancement of the patella by complete mobilisation of the patellar tendon, lateral release and advancement of vastus medialis obliquus. The long-term results were assessed radiologically, clinically and functionally using the Lysholm knee score, by an independent observer. The mean age at operation was 10.3 years (7 to 14) with a mean follow-up of 13.5 years (11 to 16). One patient required revision. At the latest follow-up, all patellae were stable and knees functional with a mean Lysholm knee score of 98 points (95 to 100). In those aged younger than ten years at operation there was a statistically significant improvement in the sulcus angle at the latest follow-up (Student's t-test, p = 0.001). Two patients developed asymptomatic patella infera as a late complication. This technique offers a satisfactory treatment for the immature patient presenting with habitual patellar dislocation associated with patella alta. If performed early, we believe that remodelling of the shallow trochlea may occur, adding intrinsic patellofemoral stability.

Pheromonostasis is not directly associated with post-mating sperm dynamics in Choristoneura fumiferana and C. rosaceana females.

In Lepidoptera, a number of humoral and neural cues are involved in post-mating pheromonostasis, including the presence of sperm in the spermatheca. However, as there are two types of sperm, apyrene and eupyrene, they may play different roles in pheromonostasis, an aspect not considered in previous studies. As a first step to examine this possibility, we determined the quantity of sperm transferred by the male at the time of mating and the temporal migration of both sperm types from the bursa copulatrix to the spermatheca in the spruce budworm, Choristoneura fumiferana, and the obliquebanded leafroller, C. rosaceana. While the mass of the ejaculate was positively correlated to male body mass, there was no relation between ejaculate mass and sperm numbers. In both species, the migration of the two sperm types was asynchronous, with the apyrene sperm migrating before the eupyrene type. There were, however, some interspecific temporal differences in the migration of both sperm types. Eupyrene sperm would not serve as a direct signal for pheromonostasis in either species as it does not reach the spermatheca for at least 7 h while the neural message for pheromonostasis in both tortricids occurs within 3 h of mating. Given the time apyrene sperm arrives in the spermatheca (between 3 and 5 h post-mating), it could serve as a direct cue for pheromonostasis in C. fumiferana but not in C. rosaceana. However, considering that these two Choristoneura species have similar pheromone physiologies, it seems somewhat unlikely that apyrene sperm would be involved in one species and not the other.

Age-related changes in the competency of the pheromone gland and the pheromonotropic activity of the brain of both virgin and mated females of two Choristoneura species.

Nine-day-old decapitated females injected with different doses of Hez-PBAN produced significantly less pheromone than 1-day-old individuals, suggesting that the age-related decline in the pheromone titre of Choristoneura fumiferana and C. rosaceana virgin females was primarily the result of a reduced ability of the glands to produce pheromone. In C. fumiferana, lower pheromonotropic activity of the Br-SEG may also contribute to the pheromone decline with age but not in C. rosaceana, as the pheromonotropic activity of the Br-SEG remained constant throughout the females' life. In both Choristoneura species, mating also suppressed pheromone production (pheromonostasis) after 24 h. The Br-SEG of mated females contained PBAN but there was no indication that its concentration changed with time post-mating since Br-SEG homogenates obtained from different-aged mated females showed the same level of pheromonotropic activity in both Choristoneura species. However, as observed in virgins, pheromone glands of older mated females were less sensitive to PBAN than those of younger ones. This suggests that the probability of Choristoneura females to attract a second mate may decrease with an increase in the refractory period following the first mating.

Coexpression of rat glutathione S-transferase A3 and human cytidine deaminase by a bicistronic retroviral vector confers in vitro resistance to nitrogen mustards and cytosine arabinoside in murine fibroblasts.

The transfer of drug resistance genes into hematopoietic cells is an experimental approach to protect patients from drug-induced myelosuppression. Because anti-cancer drugs are often administered in combination to increase their clinical efficacy, vectors that express two drug resistance genes are being developed to broaden the spectrum of chemoprotection. We have constructed a bicistronic vector, MFG/GST-IRES-CD (MFG/GIC) coexpressing rat glutathione S-transferase (GST) A3 isoform (rGST Yc1) and human cytidine deaminase (CD). Murine NIH 3T3 fibroblast cells transduced with this vector were evaluated for their resistance to nitrogen mustards and cytosine nucleoside analogs. GIC-transduced polyclonal cell populations (GIC cells) demonstrated marked increases in selenium-independent glutathione peroxidase (peroxidase) and CD activities, as well as increased resistance to melphalan (2.3-fold), chlorambucil (3.4-fold), and cytosine arabinoside (Ara-C) (8.1-fold). After selection with Ara-C, the peroxidase and CD activities of GIC cells were augmented 2.6- and 2.9-fold, respectively, in comparison with unselected cells, and the resistance to melphalan, chlorambucil, and Ara-C was further increased to 3.7-, 5.9-, and 53-fold, respectively. Melphalan selection of GIC cells likewise augmented their peroxidase (2.3-fold) and CD (1.9-fold) activities. GIC cells proliferated in the simultaneous presence of melphalan and Ara-C at drug concentrations that completely inhibited the growth of untransduced cells. The growth rate of unselected GIC cells exposed to the drug combination averaged 18% that of drug-free cultures. The growth rate of GIC cells exposed to the drug combination increased to 30% of controls after Ara-C selection and to 50% after melphalan selection. Our results suggest that retroviral transfer of MFG/GIC may be useful for chemoprotection against the toxicities of nitrogen mustards and cytosine nucleoside analogs.

Regulation of pheromone inhibition in mated females of Choristoneura fumiferana and C. rosaceana.

In the spruce budworm, Choristoneura fumiferana, and the obliquebanded leafroller, C. rosaceana, mating significantly depressed pheromone production after 24 h. On subsequent days, the pheromone titre increased slightly in C. fumiferana, but not in C. rosaceana. No pheromonostatic activity was associated with male accessory sex gland (ASG) extracts, 20-hydroxy-ecdysone or hemolymph taken from mated females. However, pheromone production in mated females was not suppressed when the ventral nerve cord (VNC) was transected prior to mating, indicating that an intact VNC is required to permanently switch off pheromone production after mating. As suggested for other moth species, the presence of sperm in the spermatheca probably triggers the release of a signal, via the VNC, to inhibit pheromone production. The fact that in both species the brain-suboesophageal ganglion (Br-SEG) of mated females contains pheromonotropic activity and that their pheromone glands may be stimulated by the synthetic pheromone-biosynthesis-activating-neuropeptide (PBAN) or a brain extract supports the hypothesis that the neural signal prevents the release of PBAN into the hemolymph rather than inhibiting its biosynthesis. Therefore, we speculate that following the depletion of sperm in the spermatheca, the neural signal declines and is less effective in preventing the release of PBAN, thereby stimulating the resumption of pheromone production, as seen in mated C. fumiferana females. In a previous study, mating was shown to induce a significant rise in the juvenile hormone (JH) titre of both Choristoneura female moths, suggesting that post-mating pheromone inhibition may be under hormonal regulation. However, following topical applications or injections of the juvenile hormone analogue (JHA) and JH II into virgins, the pheromone only declined significantly 48 h after treatment in C. rosaceana. This suggests that the significant rise in the hemolymph JH titre after mating in C. rosaceana females plays a role in keeping the pheromone titre consistently low throughout their reproductive life. These findings will be discussed in relation to the different life histories of the two Choristoneura species.

Physiological control of pheromone production in Choristoneura fumiferana and C. rosaceana.

The diel periodicity of calling behavior and pheromone production are synchronous in virgin females of both Choristoneura fumiferana and C. rosaceana (Lepidoptera: Tortricidae). Newly emerged females decapitated prior to scotophase produced no or very little pheromone 24 h later. However, injection of PBAN or Br-SEG homogenates, obtained from donors of the same or the other species, stimulated pheromone production to normal levels. Transection of the ventral nerve cord (VNC) or extirpation of the terminal abdominal ganglion (TAG) did not affect pheromone production in control females. Similarly, injections of PBAN or Br-SEG homogenates into decapitated females reactivated pheromone production to normal levels, whether or not the VNC was intact or the TAG present. Furthermore, octopamine was not effective in stimulating pheromone production in decapitated females. Taken together, these results indicate that the regulation of pheromone production is not neurally mediated in either Choristoneura species. However, there was no evidence that hemolymph collected from pheromone-producing females contained pheromonotropic activity. Similarly, isolated glands incubated with PBAN did not produce pheromone. The presence of the bursa copulatrix was required to produce pheromone in both tortricids as production was not restored in decapitated bursa-less females injected with PBAN or a Br-SEG homogenate. However, an extract of the bursa copulatrix did not elicit pheromonotropic activity in decapitated females or incubated glands of either species. The bursa copulatrix is only involved in pheromone production of some species of tortricids but our results do not support the current explanation for such interspecific differences. We postulate that the relative importance of a bursa factor may be related to the evolution of different desaturation systems used for pheromone biosynthesis in the Tortricidae. Arch.