Ensuring quality in 17OHP mass spectrometry measurement: an international study assessing isomeric steroid interference.

OBJECTIVES: Interference from isomeric steroids is a potential cause of disparity between mass spectrometry-based 17-hydroxyprogesterone (17OHP) results. We aimed to assess the proficiency of mass spectrometry laboratories to report 17OHP in the presence of known isomeric steroids. METHODS: A series of five samples were prepared using a previously demonstrated commutable approach. These samples included a control (spiked to 15.0 nmol/L 17OHP) and four challenge samples further enriched with equimolar concentrations of 17OHP isomers (11α-hydroxyprogesterone, 11ß-hydroxyprogesterone, 16α-hydroxyprogesterone or 21-hydroxyprogesterone). These samples were distributed to 38 participating laboratories that reported serum 17OHP results using mass spectrometry in two external quality assurance programs. The result for each challenge sample was compared to the control sample submitted by each participant. RESULTS: Twenty-six laboratories (68 % of distribution) across three continents returned results. Twenty-five laboratories used liquid chromatography-tandem mass spectrometry (LC-MS/MS), and one used gas chromatography-tandem mass spectrometry to measure 17OHP. The all-method median of the control sample was 14.3 nmol/L, ranging from 12.4 to 17.6 nmol/L. One laboratory had results that approached the lower limit of tolerance (minus 17.7 % of the control sample), suggesting the isomeric steroid caused an irregular result. CONCLUSIONS: Most participating laboratories demonstrated their ability to reliably measure 17OHP in the presence of the four clinically relevant isomeric steroids. The performance of the 12 (32 %) laboratories that did not engage in this activity remains unclear. We recommend that all laboratories offering LC-MS/MS analysis of 17OHP in serum, plasma, or dried bloodspots determine that the isomeric steroids are appropriately separated.

Specificities of Meningitis and Meningo-Encephalitis After Kidney Transplantation: A French Retrospective Cohort Study.

Kidney transplant recipients develop atypical infections in their epidemiology, presentation and outcome. Among these, meningitis and meningoencephalitis require urgent and adapted anti-infectious therapy, but published data is scarce in KTRs. The aim of this study was to describe their epidemiology, presentation and outcome, in order to improve their diagnostic and management. We performed a retrospective, multicentric cohort study in 15 French hospitals that included all 199 cases of M/ME in KTRs between 2007 and 2018 (0.9 case per 1,000 KTRs annually). Epidemiology was different from that in the general population: 20% were due to Cryptococcus neoformans, 13.5% to varicella-zoster virus, 5.5% to Mycobacterium tuberculosis, and 4.5% to Enterobacteria (half of which produced extended spectrum beta-lactamases), and 5% were Post Transplant Lymphoproliferative Disorders. Microorganisms causing M/ME in the general population were infrequent (2%, for Streptococcus pneumoniae) or absent (Neisseria meningitidis). M/ME caused by Enterobacteria, Staphylococci or filamentous fungi were associated with high and early mortality (50%-70% at 1 year). Graft survival was not associated with the etiology of M/ME, nor was impacted by immunosuppression reduction. Based on these results, we suggest international studies to adapt guidelines in order to improve the diagnosis and the probabilistic treatment of M/ME in SOTRs.

Tapering of Etanercept is feasible in patients with Rheumatoid Arthritis in sustained remission: a pragmatic randomized controlled trial.

OBJECTIVE: In patients with rheumatoid arthritis (RA) in sustained remission, tapering of biological disease-modifying anti-rheumatic drugs can be considered. Tapering has already been investigated, but its feasibility remains to be determined. Therefore, we explored the feasibility of tapering etanercept in RA in a setting close to practice. METHOD: Patients with RA in 28-joint Disease Activity Score (DAS28) remission (≥ 6 months) and treated with etanercept 50 mg weekly (≥ 1 year) were included in the pragmatic 1 year open-label multicentre randomized controlled TapERA (Tapering Etanercept in Rheumatoid Arthritis) trial. Patients were assigned to continue etanercept weekly or to taper to every other week (EOW). Patients who lost remission [DAS28-C-reactive protein (CRP) ≥ 2.6] were re-escalated to etanercept weekly. The primary outcome was the proportion of patients maintaining DAS28-CRP remission for 6 months. RESULTS: Sixty-six patients were randomized to etanercept weekly (n = 34) or EOW (n = 32). After 6 months, 26/34 patients (76%) in the weekly and 19/32 (59%) in the EOW group maintained disease control (p = 0.136). In the EOW group, 20/32 patients (63%) remained on their tapered treatment during the trial. Two patients reintroduced weekly etanercept themselves. Ten patients were re-escalated to etanercept weekly by the rheumatologist, after a median (interquartile range) interval of 3.0 (2.0-6.0) months. Among these patients, 7/10 regained remission after re-escalation, four of them at the next study visit. CONCLUSIONS: Although non-inferiority could not be demonstrated, tapering of etanercept to EOW appeared feasible in patients in sustained remission.

Belgian rheumatologists' preferences regarding measures of disease activity in patients with rheumatoid arthritis: results from a mixed-methods study.

The reliability and clinical usefulness of the different composite disease activity scores and their individual components in Rheumatoid Arthritis (RA) are still debated. This study investigated which measures of disease activity were preferred by rheumatologists. A mixed-method study was performed. First, ten Belgian rheumatologists were invited for individual interviews on their current practice and preferences for measurement of RA disease activity. Results of this qualitative study and evidence from literature served as input for developing a survey. This survey asked rheumatologists to rate preferred standard disease activity score(s), their individual components, ultrasound and related patient-reported outcomes (PROs), by maximum difference scaling. The relative importance score (RIS) for each indicator was calculated using hierarchical Bayes modeling. The qualitative study included 6/10 invited rheumatologists. Composite scores and components were perceived as useful, while PROs were found subjective. Interestingly, ultrasound was used to mediate discrepancies between physician and patient. The survey based on this was sent to 244 Belgian rheumatologists, 83/244 (34%) responded, including 66/83 (80%) complete and 17/83 (20%) incomplete surveys (two missing essential information). Most rheumatologists (75/81, 93%) used a disease activity score and 68/81 (84%) preferred the DAS28-CRP. Swollen joint count obtained the highest mean ± SD RIS (22.54 ± 2.64), followed by DAS28 ESR/CRP (20.61 ± 4.06), ultrasound (16.47 ± 7.97), CRP (13.34 ± 6.11) and physician's global assessment (12.59 ± 7.83). PROs including fatigue, pain, and patient's global assessment, and Health Assessment Questionnaire, obtained the lowest mean RIS (0.34-2.54). Rheumatologists place more faith in self-assessed disease activity components or in laboratory tests. Trust in PROs to evaluate disease activity is low in clinical practice.

Is intraoperative heparin during renal transplantation useful to reduce graft vascular thrombosis?

OBJECTIVES: The standard treatment for end-stage renal disease is renal transplantation. As vascular anastomoses are performed during the surgery, it may expose to a risk of vascular thrombosis. This raises the question of using intravenous heparin during the procedure. The purpose of this study was to compare the incidence of renal transplant vascular thrombosis in the perioperative period based on whether the patients received or not intraoperative heparin. METHODS: A single center retrospective study was conducted on a cohort of consecutive patients who underwent renal transplantation between 2011 and 2015. Patients were divided into two groups: patients not receiving heparin vs. receiving heparin at the dose of 0.5mg/kg. A Doppler ultrasound was performed at day one postoperatively to assess the occurrence of vascular thrombosis. Hemorrhagic complications and the need for postoperative transfusion were also assessed. RESULTS: In total, 261 patients were included. Fifty-one patients received heparin (19.5%). Patient's baseline characteristics were comparable between the groups. No significant difference was found regarding the incidence of vascular thrombosis (6% for both groups, P=1). In addition, no difference was found regarding hemorrhagic complications requiring surgical revision (P=1) as well as early postoperative transfusion rate (P=0.57). CONCLUSIONS: Our results suggest that intraoperative IV heparin doesn't improve the risk of vascular thrombosis following renal transplantation. However, intraoperative IV heparin was not significantly associated with a higher rate of hemorrhagic complications suggesting that heparin can be safely used if required in some selected patients at higher risk of thrombosis. LEVEL OF EVIDENCE: 3.

[Continuing professional development and recertification process in France]. / Développement professionnel continu (DPC) et émergence de la recertification en France. Évolution législative et commentaires.

Continuing medical education (CME) is an obligation in France. The evaluation of professional practices joined in 2004 the obligation to acquire knowledge, becoming the Continuing professional development (CPD) in 2009. Currently, the system is complete: definition, organization and validation. However, the individual obligation to validate the CPD has never been applied. The recertification process provided for by the 2019 law will not be operational until 2021, at the earliest. Its essential pillar is CPD. The recertification mission who prepared the law excludes all knowledge verification tests. Recertification is done by promoting the professional career path including, in addition to CPD, a maintained and regular activity, an improvement in the relationship with the patient, taking into account the doctor's health and the absence of undesirable events. Seeing that the French Medical Council oversees the professional skills of physicians, it is the Council that receives the validation of the CPD and will receive that of recertification.

When results matter: reliable creatinine concentrations in hyperbilirubinemia patients.

Background Failure to report a creatinine concentration, especially in icteric patients who are eligible for a liver transplant, can result in a life-threatening situation. We assessed the influence of bilirubin interference on several creatinine assays and investigated ways to circumvent icteric interference without interfering with our normal automated sample logistics. Methods Using icteric patient sera (total bilirubin >255 µmol/L) we determined creatinine concentrations using an enzymatic and Jaffé assay (Roche Diagnostics) in both normal (i.e. undiluted) and decreased mode (i.e. diluted) as well as an enzyme-coupled amperometric assay on a Radiometer ABL837 FLEX analyzer. Creatinine concentrations from the five methods were compared with an in-house developed LC-MS/MS method. Passing and Bablok (proportional and constant bias) as well as difference plot parameters (bias and 95% limits of agreement [LoA]) were calculated. Interferograph-based regression analysis of the enzymatic and Jaffé results was used to investigate if such an approach could be used to report corrected creatinine concentrations in icteric patient sera. Results In icteric patient sera the enzyme-coupled amperometric assay was hardly influenced by icteric interference as shown by a difference plot bias of -1.5% (95% LoA -11.6 to +8.5%). The undiluted Jaffé method had a bias of -1.4% with a very broad 95% LoA (-35.1 to +32.2%) emphasizing the poor specificity of this method. The undiluted enzymatic method had the largest bias (-13.4%, 95% LoA -35.8 to +9.0%). Diluting sera in the enzymatic method did not improve the bias (-10.5%, 95% LoA -25.4 to 4.4%), while diluting the Jaffé method resulted in a bias increase (+11.4%, 95% LoA -14.7 to 37.5%). Using interferograph-based regression analysis we were able to reliably correct enzymatic creatinine concentrations in 97 out of 100 icteric patient sera. Conclusions Analytically, quantifying creatinine in icteric sera using the Radiometer ABL837 FLEX analyzer is the method of choice within our laboratory. However, not all laboratories are equipped with this method and even if available, the limited number of highly icteric patient sera makes this method costly. For those laboratories using the Roche enzymatic method, mathematically correcting an icteric creatinine concentration using an interferograph based on an LC-MS/MS reference method is a suitable alternative to report reliable creatinine results in icteric patients.

Association between methylation potential and nutrient metabolism throughout the reproductive cycle of sows.

DNA methylation is an important epigenetic strategy for embryo development and survival. The one-carbon metabolism can be disturbed by inadequate provision of dietary methyl donors. Because of the continuous selection for larger litters, it is relevant to explore if highly prolific sows might encounter periods of methyl donor deficiency throughout their reproductive cycles. This study, therefore, assesses the fluctuation(s) in methylation potential (MP) and aims to link possible methyl donor deficiencies to nutrient metabolism. In total, 15 hybrid sows were followed from weaning of the previous reproductive cycle (d-5) to weaning of the present cycle. Blood samples were taken at d-5, 0, 21, 42, 63, 84 and d108 of gestation, the day of parturition (d115), two weeks of lactation (d129) and at weaning (d143). Blood plasma samples were analysed for S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), free methionine, free glycine, acetylcarnitine and 3-hydroxybutyrylcarnitine. Serum samples were analysed for urea and creatinine. Generally, MP (i.e. ratio SAM:SAH) increased throughout gestation (p = 0.009), but strongly fluctuated in the period around parturition and weaning. From d108 to parturition, absolute plasma levels of SAM (p < 0.001), SAH (p = 0.031) and methionine (p = 0.001) increased. The first two weeks of lactation were characterised by an increase in MP (p = 0.039) due to a remaining high value of SAM and a distinct decrease in SAH (p = 0.008). During the last two weeks of lactation, MP decreased (p = 0.038) due to a decrease in SAM (p < 0.001) and a stable value for SAH. The methylation reactions seem to continue after weaning, a period crucial for the follicular and embryonic development of the subsequent litter. This study thus demonstrates that the methylation status fluctuates substantially throughout a sow's reproductive cycle, and further research is needed to identify the factors affecting methylation status.

All naturally occurring autoantibodies against the NMDA receptor subunit NR1 have pathogenic potential irrespective of epitope and immunoglobulin class.

Autoantibodies of the IgG class against N-methyl-d-aspartate-receptor subunit NR1 (NMDAR1) were first described in anti-NMDAR encephalitis and seen as disease indicators. Recent work on together over 5000 individuals challenged this exclusive view by showing age-dependently up to >20% NMDAR1-autoantibody seroprevalence with comparable immunoglobulin class and titer distribution across health and disease. The key question therefore is to understand the properties of these autoantibodies, also in healthy carriers, in order to assess secondary complications and possible contributions to neuropsychiatric disease. Here, we believe we provide for human NMDAR1-autoantibodies the first comprehensive analysis of their target epitopes and functionality. We selected sera of representative carriers, healthy or diagnosed with very diverse conditions, that is, schizophrenia, age-related disorders like hypertension and diabetes, or anti-NMDAR encephalitis. We show that all positive sera investigated, regardless of source (ill or healthy donor) and immunoglobulin class, provoked NMDAR1 internalization in human-induced pluripotent stem cell-derived neurons and reduction of glutamate-evoked currents in NR1-1b/NR2A-expressing Xenopus oocytes. They displayed frequently polyclonal/polyspecific epitope recognition in the extracellular or intracellular NMDAR1 domains and some additionally in NR2A. We conclude that all circulating NMDAR1-autoantibodies have pathogenic potential regarding the whole spectrum of neuronal NMDAR-mediated effects upon access to the brain in situations of increased blood-brain-barrier permeability.

Belatacept Rescue Therapy in Kidney Transplant Recipients With Vascular Lesions: A Case Control Study.

Immunosuppression in kidney transplant recipients with decreased graft function and severe histological vascular changes can be particularly challenging. Belatacept could be a valuable option, as a rescue therapy in this context. We report a retrospective case control study comparing a CNI to belatacept switch in 17 patients with vascular damage and low eGFR to a control group of 18 matched patients with CNI continuation. Belatacept switch was performed on average 51.5 months after kidney transplantation (6.2-198 months). There was no difference between the two groups regarding eGFR at inclusion, and 3 months before inclusion. In the "CNI to belatacept switch group," mean eGFR increased significantly from 23.5 ± 6.7 mL/min/1.73m2 on day 0, to 30.4 ± 9.1 mL/min/1.73 m2 on month 6 (p < 0.001) compared to the control group, in which no improvement was observed. These results were still significant on month 12. Two patients experienced biopsy-proven acute rejection. One was effectively treated without belatacept discontinuation. Two patients needed belatacept discontinuation for infection. In conclusion, the remplacement of CNI with belatacept in patients with decreased allograft function and vascular lesions is associated with an improvement in eGFR.

Reduction of Extended-Release Tacrolimus Dose in Low-Immunological-Risk Kidney Transplant Recipients Increases Risk of Rejection and Appearance of Donor-Specific Antibodies: A Randomized Study.

The aim of this study (ClinicalTrials.gov, NCT01744470) was to determine the efficacy and safety of two different doses of extended-release tacrolimus (TacER) in kidney transplant recipients (KTRs) between 4 and 12 mo after transplantation. Stable steroid-free KTRs were randomized (1:1) after 4 mo: Group A had a 50% reduction in TacER dose with a targeted TacER trough level (C0 ) >3 µg/L; group B had no change in TacER dose (TacER C0 7-12 µg/L). The primary outcome was estimated GFR at 1 year. Of 300 patients, the intent-to-treat analysis included 186 patients (group A, n = 87; group B, n = 99). TacER C0 was lower in group A than in group B at 6 mo (4.1 ± 2.7 vs. 6.7 ± 3.9 µg/L, p < 0.0001) and 12 mo (5.6 ± 2.0 vs. 7.4 ± 2.1 µg/L, p < 0.0001). Estimated GFR was similar in both groups at 12 mo (group A, 56.0 ± 17.5 mL/min per 1.73 m²; group B, 56.0 ± 22.1 mL/min per 1.73 m²). More rejection episodes occurred in group A than group B (11 vs. 3; p = 0.016). At 1 year, subclinical inflammation occurred more frequently in group A than group B (inflammation score [i] >0: 21.4% vs. 8.8%, p = 0.047; tubulitis score [t] >0: 19.6% vs. 8.7%, p = 0.076; i + t: 1.14 ± 1.21 vs. 0.72 ± 1.01, p = 0.038). Anti-HLA donor-specific antibodies appeared only in group A (6 vs. 0 patients, p = 0.008). TacER C0 should be maintained >7 µg/L during the first year after transplantation in low-immunological-risk, steroid-free KTRs receiving a moderate dose of mycophenolic acid.

Effect of an Early Switch to Belatacept Among Calcineurin Inhibitor-Intolerant Graft Recipients of Kidneys From Extended-Criteria Donors.

Transplant recipients receiving a kidney from an extended-criteria donor (ECD) are exposed to calcineurin inhibitor (CNI) nephrotoxicity, as demonstrated by severe delayed graft function and/or a low GFR. Belatacept is a nonnephrotoxic drug that is indicated as an alternative to CNIs. We reported 25 cases of conversion from a CNI to belatacept due to CNI intolerance within the first 6 mo after transplantation. The mean age of the recipients was 59 years, and 24 of 25 patients received ECD kidneys. At the date of the medication switch, 12 of 25 patients displayed a calculated GFR (cGFR) <15 mL/min, six patients remained on dialysis, and the biopsies showed evidence of acute tubular damage associated with severe vascular or tubulointerstitial chronic lesions. Three patients did not recover renal function, and three patients died during the follow-up period. Among the remaining patients, renal function improved: The cGFR was 18.28 ± 12.3 mL/min before the medication switch compared with 34.9 ± 14.5 mL/min at 1 year after conversion to belatacept (p = 0.002). Tolerance of and compliance with belatacept were good, and only one patient experienced acute rejection. Belatacept is an effective therapy that preserves renal function in kidney transplant patients who are intolerant of CNIs.

A multicenter comparison of whole blood vitamin B6 assays.

BACKGROUND: The aim of this study was to compare different analytical methods that are currently in use in the Netherlands for the measurement of whole blood vitamin B6. METHODS: This method comparison study consisted of two separate parts. (1) Four laboratories participated in a pilot study in which the commercial Chromsystems and INstruchemie method, and a laboratory developed liquid chromatography-tandem mass spectrometry (LC-MS/MS) method and HPLC method were compared. Sixty-nine frozen whole blood samples and six lyophilized whole blood samples were used for comparison. (2) In the nationwide part of the study, 49 laboratories participated in the analysis of three identical sets of two whole blood samples of which one set was freshly analyzed, one set was analyzed after storage at -20 °C and one set was analyzed after lyophilization. RESULTS: In both parts of the study, the HPLC and LC-MS/MS methods showed equivalent results for all sample types tested. The Chromsystems method showed a positive bias of 45% (pilot study) and 30% (nationwide study) towards the LC-MS/MS method when fresh or frozen samples were used. The measurement of lyophilized samples showed no differences between the methods. The results of the INstruchemie method were inconclusive due to the low number of participants. CONCLUSIONS: The different analytical methods for measuring vitamin B6 produce different results when whole blood patient samples are measured. The recognition of a reference method or the development of suitable reference materials and quality control materials might serve as a first step towards improved standardization or harmonization of the whole blood vitamin B6 assay.

Assembly of the respiratory mucin MUC5B: a new model for a gel-forming mucin.

Mucins are essential components in mucus gels that form protective barriers at all epithelial surfaces, but much remains unknown about their assembly, intragranular organization, and post-secretion unfurling to form mucus. MUC5B is a major polymeric mucin expressed by respiratory epithelia, and we investigated the molecular mechanisms involved during its assembly. Studies of intact polymeric MUC5B revealed a single high affinity calcium-binding site, distinct from multiple low affinity sites on each MUC5B monomer. Self-diffusion studies with intact MUC5B showed that calcium binding at the protein site catalyzed reversible cross-links between MUC5B chains to form networks. The site of cross-linking was identified in the MUC5B D3-domain as it was specifically blocked by D3 peptide antibodies. Biophysical analysis and single particle EM of recombinant MUC5B N terminus (D1D2D'D3; NT5B) and subdomains (D1, D1-D2, D2-D'-D3, and D3) generated structural models of monomers and disulfide-linked dimers and suggested that MUC5B multimerizes by disulfide linkage between D3-domains to form linear polymer chains. Moreover, these analyses revealed reversible homotypic interactions of NT5B at low pH and in high calcium, between disulfide-linked NT5B dimers, but not monomers. These results enable a model of MUC5B to be derived, which predicts mechanisms of mucin intracellular assembly and storage, which may be common to the other major gel-forming polymeric mucins.

Immune Reconstitution Inflammatory Syndrome Secondary to Mycobacterium kansasii Infection in a Kidney Transplant Recipient.

Nontuberculous mycobacteria (NTM) infection is a challenging diagnosis for clinicians in solid organ transplantation. Immune reconstitution inflammatory syndrome (IRIS) is so far unreported in this context. We report here the case of a renal transplant recipient who developed Mycobacterium kansasii-associated lymphadenitis complicated by IRIS while undergoing reduction of his immunosuppressive therapy. For IRIS, the patient required low-dose steroids and an increase in global immunosuppression, in association with NTM antibiotherapy.

Early life poly- and perfluoroalkyl substance levels and adiposity in the first 2 years of life.

IMPORTANCE: Poly- and perfluoroalkyl substances (PFASs) are nondegradable, man-made chemicals. They accumulate in humans with potential harmful effects, especially in susceptible periods of human development, such as the first months of life. We found that, in our cohort, exclusively breastfed (EBF) infants had 3 times higher PFAS plasma levels compared with exclusively formula-fed (EFF) infants at the age of 3 months. Thus, PFASs could potentially reduce the health benefits of breastfeeding. OBJECTIVE: We investigated the associations between PFAS levels at the age of 3 months and accelerated gain in fat mass during the first 6 months of life, body composition at 2 years, and whether these associations differ between EBF and EFF infants. SETTING: In 372 healthy term-born infants, we longitudinally assessed anthropometrics, body composition (by air-displacement plethysmography and dual-energy X-ray absorptiometry), and visceral and subcutaneous fat (by abdominal ultrasound) until the age of 2 years. MEASURES: The plasma levels of 5 individual PFASs were determined by liquid chromatography-electrospray ionization-tandem mass spectrometry at the age of 3 months. MAIN OUTCOMES: We studied associations between PFAS levels and outcomes using multiple regression analyses. RESULTS: Higher early life plasma perfluorooctanoic acid and total PFAS levels were associated with an accelerated gain in fat mass percentage [FM%; >0.67 SD score (SDS)] during the first 6 months of life. Higher early life PFAS levels were associated with lower fat-free mass (FFM) SDS at the age of 2 years, but not with total FM% SDS at 2 years. Furthermore, we found opposite effects of PFAS levels (negative) and exclusive breastfeeding (positive) at the age of 3 months on FFM SDS at 2 years. CONCLUSION: Higher PFAS levels in early life are associated with accelerated gains in FM% during the first 6 months of life and with lower FFM SDS at the age of 2 years, which have been associated with an unfavorable body composition and metabolic profile later in life. Our findings warrant further research with longer follow-up times.

Search for dark matter annihilations in the sun with the 79-string IceCube detector.

We have performed a search for muon neutrinos from dark matter annihilation in the center of the Sun with the 79-string configuration of the IceCube neutrino telescope. For the first time, the DeepCore subarray is included in the analysis, lowering the energy threshold and extending the search to the austral summer. The 317 days of data collected between June 2010 and May 2011 are consistent with the expected background from atmospheric muons and neutrinos. Upper limits are set on the dark matter annihilation rate, with conversions to limits on spin-dependent and spin-independent scattering cross sections of weakly interacting massive particles (WIMPs) on protons, for WIMP masses in the range 20-5000 GeV/c2. These are the most stringent spin-dependent WIMP-proton cross section limits to date above 35 GeV/c2 for most WIMP models.

Measurement of atmospheric neutrino oscillations with IceCube.

We present the first statistically significant detection of neutrino oscillations in the high-energy regime (>20 GeV) from an analysis of IceCube Neutrino Observatory data collected in 2010 and 2011. This measurement is made possible by the low-energy threshold of the DeepCore detector (~20 GeV) and benefits from the use of the IceCube detector as a veto against cosmic-ray-induced muon background. The oscillation signal was detected within a low-energy muon neutrino sample (20-100 GeV) extracted from data collected by DeepCore. A high-energy muon neutrino sample (100 GeV-10 TeV) was extracted from IceCube data to constrain systematic uncertainties. The disappearance of low-energy upward-going muon neutrinos was observed, and the nonoscillation hypothesis is rejected with more than 5σ significance. In a two-neutrino flavor formalism, our data are best described by the atmospheric neutrino oscillation parameters |Δm(32)(2)|=(2.3(-0.5)(+0.6))×10(-3) eV(2) and sin(2)(2θ(23))>0.93, and maximum mixing is favored.