Evaluation of Genetic or Cellular Impairments in Type I IFN Immunity in a Cohort of Young Adults with Critical COVID-19.

Several genetic and immunological risk factors for severe COVID-19 have been identified, with monogenic conditions relating to 13 genes of type I interferon (IFN) immunity proposed to explain 4.8% of critical cases. However, previous cohorts have been clinically heterogeneous and were not subjected to thorough genetic and immunological analyses. We therefore aimed to systematically investigate the prevalence of rare genetic variants causing inborn errors of immunity (IEI) and functionally interrogate the type I IFN pathway in young adults that suffered from critical COVID-19 yet lacked comorbidities. We selected and clinically characterized a cohort of 38 previously healthy individuals under 50 years of age who were treated in intensive care units due to critical COVID-19. Blood samples were collected after convalescence. Two patients had IFN-α autoantibodies. Genome sequencing revealed very rare variants in the type I IFN pathway in 31.6% of the patients, which was similar to controls. Analyses of cryopreserved leukocytes did not indicate any defect in plasmacytoid dendritic cell sensing of TLR7 and TLR9 agonists in patients carrying variants in these pathways. However, lymphocyte STAT phosphorylation and protein upregulation upon IFN-α stimulation revealed three possible cases of impaired type I IFN signaling in carriers of rare variants. Together, our results suggest a strategy of functional screening followed by genome analyses and biochemical validation to uncover undiagnosed causes of critical COVID-19.

Association of Knee Osteoarthritis and Flexion Contracture With Localized Tibial Articular Cartilage Loss: Data From the Osteoarthritis Initiative.

OBJECTIVE: To evaluate whether a knee flexion contracture (FC) was associated with localized tibial articular cartilage loss over a 1-year period using Osteoarthritis Initiative quantitative data. METHODS: Five hundred seventy-eight participants from a previously established nested case-control study of people with radiographic knee OA with or without progression, based on radiographs and symptoms, had their knee range of extension measured at baseline and received magnetic resonance imaging (MRI) at baseline and 1 year. The tibial articular cartilage of the medial and lateral condyles was segmented into anterior, center, and posterior regions. We tested for associations between knee FC (defined as lack of extension to 0°), and localized changes in tibial articular cartilage thickness or percent of denuded bone (0 mm thickness) after 1 year relative to baseline using ANOVA, controlling for baseline MRI outcomes and clinical factors. RESULTS: Knee FC was associated with denuded bone in the medial condyle center (ß 0.44, 95% CI 0.02-0.86) and preserved cartilage thickness in the medial condyle posterior (ß 0.01, 95% CI 0.002-0.03) regions. CONCLUSION: Knee FC unloading the tibial center region and loading the posterior region was associated with localized articular cartilage loss centrally and preserved articular cartilage posteriorly. These findings are consistent with knee FC negatively affecting unloaded tibial articular cartilage.

Soluble low affinity nerve growth factor receptor (sLNGFR) may regulate pain in knee osteoarthritis.

OBJECTIVES: Nerve growth factor ß (ß-NGF) is a protein which is important to the development of neurons particularly those involved in the transmission of pain and is central to the experience of pain in osteoarthritis (OA). Direct NGF antagonism has been shown to reduce OA pain but is associated with rapidly progressive OA. The aim of the study is to investigate the ability of soluble neurotrophin receptors in the NGF pathway to modulate pain in OA. METHODS: Synovial fluid (SF) was obtained from the knee joints of 43 subjects who underwent total knee arthroplasty. Visual analogue scale (VAS) pain scores were obtained prior to surgery. Customised-automated-ELISAs and commercial-ELISAs and LEGENDplex™ were used to measure soluble low-affinity nerve growth factor (LNGFR), soluble tropomyosin receptor kinase (TrkA), proNGF, ß-NGF, other neurotrophins (NT) and cytokines including inflammatory marker TNF-α. RESULTS: The VAS score positively correlated with ß-NGF (r=0.34) and there was positive association trend with neurotrophin-3 (NT-3), BDNF and negative association trend with ProNGF. sLNGFR positively correlated with VAS (r=0.33). The ß-NGF/soluble TrkA ratio showed a strong positive correlation with VAS (r=0.80). In contrast, there was no correlation between pain and the ß-NGF/sLNGFR ratio (r=-0.08). TNF-α positively correlated with ß-NGF (r=0.83), NT-3 (r=0.66), and brain-derived neurotrophic factor (BDNF) (r=0.50) and negatively with ProNGF (r= -0.74) and positively correlated with both soluble TrkA (r=0.62), sLNGFR (r=0.26). CONCLUSIONS: This study suggests that endogenous or cleaved sLNGFR, but not soluble TrkA may participate in OA pain modulation thus supporting further research into soluble LNGFR as a therapeutic target in OA.

Patient interest in and clinician reservations on polygenic embryo screening: a qualitative study of stakeholder perspectives.

PURPOSE: We explored and compared perspectives of reproductive endocrinology and infertility specialists (REIs) and in vitro fertilization (IVF) patients regarding polygenic embryo screening (PES), a new type of preimplantation screening that estimates the genetic chances of developing polygenic conditions and traits in the future. METHODS: Qualitative thematic analysis of semi-structured interviews with US-based REIs and IVF patients. RESULTS: Clinicians and patients often held favorable views of screening embryos for physical or psychiatric conditions, though clinicians tended to temper their positive attitudes with specific caveats. Clinicians also expressed negative views about screening embryos for traits more frequently than patients, who generally held more positive views. Most clinicians were either unwilling to discuss or offer PES to patients or were willing to do so only under certain circumstances, while many patients expressed interest in PES. Both stakeholder groups envisioned multiple potential benefits or uses of PES and raised multiple potential, interrelated concerns about PES. CONCLUSION: A gap exists between clinician and patient attitudes toward PES; clinicians generally maintained reservations about such screening and patients indicated interest in it. Clinicians and patients sometimes imagined using PES to prepare for the birth of a predisposed or "affected" individual-a rationale that is often associated with prenatal testing. Many clinicians and patients held different attitudes depending on what is specifically screened, despite the sometimes blurry distinction between conditions and traits. Considerations raised by clinicians and patients may help guide professional societies in developing guidelines to navigate the uncertain terrain of PES.

Baseline knee extension may be associated with volumetric cartilage loss in the anterolateral tibia: data from the Osteoarthritis Initiative.

OBJECTIVES: Animal studies suggest regional unloading of the knee due to flexion contracture (FC) results in cartilage loss in the anterior tibia. We looked for an association between the range of knee extension and articular cartilage thickness in the tibia of patients with knee OA, using quantitative MRI data from the OA Initiative. METHODS: Baseline knee extension was measured using a goniometer. Cartilage thickness was measured using 3-Tesla coronal MRI images of the knee. The tibia articular cartilage was segmented into medial and lateral regions, then further divided into anterior, central and posterior subregions. We evaluated differences between participants with and without a knee FC and associations between knee extension and cartilage thickness, including percentage denudation of bones (0 mm thickness), using linear models. RESULTS: A total of 596 participants were included. Participants with a knee FC had a larger percentage of denuded bone in the anterolateral tibia vs participants without FC (2.2 ± 0.7% vs 0.4 ± 0.1%; P = 0.006), and knee extension was associated with anterolateral tibia denuded bone (r = 0.16, P < 0.001). After correcting for demographics, knee alignment, and OA severity, presence of FC and lost knee extension were associated with the percentage of denuded bone in the anterolateral tibia [ß = 1.702 (0.634-2.770) and ß = 0.261 (95% CI 0.134, 0.388), respectively]. CONCLUSION: While causation cannot be determined in this study, limitation in knee extension was statistically associated with the percentage of denuded bone in the anterolateral tibia. These novel data support that maintaining range of motion over the entire joint surface may help preserve articular cartilage health.

Asymmetric Flexion Contracture is Associated With Leg Length Inequality in Patients With Knee Osteoarthritis: Data From the Osteoarthritis Initiative.

OBJECTIVE: To evaluate whether knee flexion contracture (FC) was associated with leg length inequality (LLI) and/or morbidity in knee osteoarthritis (OA). DESIGN: We accessed 2 databases: (1) the Osteoarthritis Initiative (OAI) cohort, including participants with, or at-risk of OA, and (2) the Ottawa Knee Osteoarthritis cross-sectional database (OKOA), including participants with primary advanced knee OA. Both included demographics, radiographic data, knee range of motion, leg length, pain, and function scales. SETTING: Tertiary care academic rheumatology and orthopedic clinics. PARTICIPANTS: Patients with or at-risk of primary OA. We included 881 OAI and 72 OKOA participants (N=953). INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: The primary outcome tested the association between the difference in knee extensions of the OA and contralateral knees (the knee extension difference, or KExD) and LLI. This was evaluated using bivariate regression, followed by a multivariable linear regression model. RESULTS: OAI participants had less severe knee OA [Kellgren and Lawrence (KL) score 1.9±1.3] vs OKOA (KL score 3.4±0.6). The KExD correlated with LLI for both databases (OAI: R=0.167; P≤.001; OKOA: R=0.339; P=.004). Multivariable regression showed an effect of KExD on LLI in both databases (OAI: ß=0.37[0.18,0.57]; P<.001, OKOA: ß=0.73[0.20,1.26]; P=.007). When broken down by subgroup, the OAI moderate-severe OA group showed a significant effect of KExD on LLI (ß=0.60 [0.34,0.85]; P<.001). CONCLUSIONS: OA-related loss of knee extension was associated with LLI for those with moderate-severe OA. Because LLI correlates with worse knee OA symptoms, discovering an FC should cue clinicians to evaluate for LLI, an easily-treatable finding that may help reduce OA-associated morbidity for those approaching the need for arthroplasty.

Flexion contracture is associated with knee joint degeneration on magnetic resonance imaging: data from the Osteoarthritis Initiative.

OBJECTIVES: Knee osteoarthritis (OA) is often accompanied by a flexion contracture (FC), resulting in worse clinical outcomes. Our objective was to determine associations between knee FC and specific regional and/or structural alterations on magnetic resonance imaging (MRI) using the Osteoarthritis Initiative (OAI). METHODS: 600 knees from the Foundation for the National Institutes of Health sub-study of the OAI were included. Knee extension was measured with a goniometer and FC was defined as inability to extend the knee to 0°. Structural alterations within the MRI Osteoarthritis Knee Score (MOAKS)-assessed regions that could potentially obstruct knee extension were primarily analysed. Multivariable linear regression models evaluated the effect size of MRI outcomes on knee extension. RESULTS: One-third (33.4%) of all participants had knee FC: 155 mild (1-5°, 26.0%), 44 moderate-severe (≥6°, 7.4%). Mean knee alignment was 0.3±3.7° valgus. Cartilage morphology and bone marrow lesion (BML) scores on the femoral side of the lateral patellofemoral joint were associated with lost knee extension (ß=0.709, p<0.001, and ß=0.666, p<0.001, respectively) as were higher osteophyte scores in multiple regions, worse meniscal score in the medial meniscal body (ß=0.164, p<0.040) and posterior horn (ß=0.400, p<0.001), and a worse effusion score (ß=0.711, p<0.001). CONCLUSIONS: Knee flexion contractures were associated with non-specific, widespread MRI degenerative changes including cartilage loss and BMLs in the lateral patellofemoral joint, osteophytes, meniscal alterations and whole-joint effusion. Loss of knee extension in OA is likely a structurally-multifactorial outcome.

Prevalence, Impact, and Treatment of Co-Occurring Osteoarthritis in Patients With Stroke Undergoing Rehabilitation: A Review.

Background and Purpose: Early, frequent rehabilitation is an important factor for optimizing stroke recovery outcomes. Medical comorbidities, such as osteoarthritis, that affect the ability to participate in rehabilitation could therefore have a detrimental impact on such outcomes. Both stroke and osteoarthritis are becoming more common in developed nations as the population ages. First-line osteoarthritis treatments, such as oral nonsteroidal anti-inflammatory drugs, are often avoided poststroke due to interaction with secondary prevention stroke risk-factor management. Our objective was to summarize the current literature concerning co-occurring osteoarthritis and stroke prevalence, its functional impact, and treatment options. Methods: Narrative review using a comprehensive literature search of PubMed, osteoarthritis, and stroke guidelines. Outcomes related to co-occurrence prevalence, osteoarthritis as a stroke risk-factor, osteoarthritis-related imaging and treatment were extracted and summarized descriptively. Overall quality of the evidence was summarized using Grading of Recommendations Assessment, Development and Evaluation. Results: We identified 23 studies and guidelines related to our objective. Overall quality of the evidence was very low. Conclusions: Few trials have investigated the relationship between osteoarthritis and stroke, nor osteoarthritis-specific pain and function management for stroke survivors. High-quality research evaluating the impact of osteoarthritis on stroke rehabilitation is needed.

Patient tolerability of suprascapular and median nerve blocks for the management of pain in post-stroke shoulder-hand syndrome.

BACKGROUND: Current management options for pain in stroke patients with the shoulder-hand syndrome (SHS) are limited and often ineffective. The use of peripheral nerve blocking in SHS has been limited due to concerns of hyperalgesia and allodynia in these patients. This study assessed the tolerability of suprascapular nerve (SSN) and median nerve blocks for acute control of pain in patients with post-stroke SHS. METHODS: All SHS patients fulfilled diagnosis using the Budapest criteria. Patient tolerability was defined by a composite score that included a change on the visual analog scale (VAS) from baseline for shoulder and hand pain, presence of adverse events, and a self-reported patient satisfaction score. Pain assessment was performed 1 h before (baseline), and 1 h and 2 weeks after the procedure. RESULTS: Five patients (68.5 ± 9.5 years) with post-stroke SHS underwent SSN and median nerve blocks. Participant assessment 1 h after the procedure indicated that the 2 blocking procedures were well tolerated and that VAS scores for shoulder and hand pain decreased by 79% (- 62.6 mm ± 25.6; p = 0.043) and 48% (- 33 mm ± 40.2; p = 0.080), respectively from baseline. After 2 weeks, average VAS scores remained 56% and 37% below baseline, respectively. There were no adverse events and all patients were satisfied after the procedure. CONCLUSIONS: Suprascapular and median nerve blocks are safe and well-tolerated procedures for acute pain control in post-stroke SHS. Further studies should address the benefit of these procedures on overall pain reduction, functional recovery, and quality of life in SHS patients.

Search for Electron Antineutrino Appearance in a Long-Baseline Muon Antineutrino Beam.

Electron antineutrino appearance is measured by the T2K experiment in an accelerator-produced antineutrino beam, using additional neutrino beam operation to constrain parameters of the Pontecorvo-Maki-Nakagawa-Sakata (PMNS) mixing matrix. T2K observes 15 candidate electron antineutrino events with a background expectation of 9.3 events. Including information from the kinematic distribution of observed events, the hypothesis of no electron antineutrino appearance is disfavored with a significance of 2.40σ and no discrepancy between data and PMNS predictions is found. A complementary analysis that introduces an additional free parameter which allows non-PMNS values of electron neutrino and antineutrino appearance also finds no discrepancy between data and PMNS predictions.

Knee Flexion Contracture Associated With a Contracture and Worse Function of the Contralateral Knee: Data From the Osteoarthritis Initiative.

OBJECTIVE: Patients at risk of developing knee osteoarthritis (OA) or those already diagnosed with knee OA may present with a knee flexion contracture (FC). A knee FC can cause pain and can decrease function. By altering lower extremity biomechanics, the effect of a knee FC goes beyond the affected joint. Compensatory movements during gait can chronically affect other joints in both lower limbs. Few studies describe the effect of a knee FC on, or direct assessment toward, the contralateral knee. We investigated the associations between knee FC with range of extension, function, pain, and stiffness of the contralateral knee. DESIGN: Cross-sectional, using the Osteoarthritis Initiative Database. PARTICIPANTS: Outpatient cohort study, recruiting from 4 United States academic health care centers (N=4796). Two groups were included: those at risk of developing OA (n=3284 knees), and those already with radiographic OA (n=1390 knees). MAIN OUTCOMES MEASURES: Maximum contralateral knee extension and Western Ontario and McMaster Osteoarthritis Index (WOMAC) scores. Statistical analysis included a mixed linear model evaluating for independent associations between the index knee FC and contralateral knee outcome measures. RESULTS: A knee FC was associated with a contralateral knee FC (P<.001) with contralateral FC severity dependent on severity of the index knee FC (P<.001). Participants at risk of developing OA with moderate FC showed worse function in the contralateral knee than those with mild FC (WOMAC functional subscale ± SD: 7.6±10.1 vs 5.5±8.8; P=.036). Mixed linear analysis confirmed an independent association between knee FC severity and contralateral WOMAC function. CONCLUSIONS: Having an FC in 1 knee was associated with an FC in the contralateral knee for participants who were at risk of developing OA and for those with a current diagnosis of OA. For those at risk of developing OA, the severity of knee FC was an independent predictor for loss of contralateral knee function. Rehabilitation of patients with or at risk of developing OA should consider the restoration of extension and function for both knees.

Tendon contains more stem cells than bone at the rotator cuff repair site.

BACKGROUND: The rotator cuff (RC) repair failure rate is high. Tendon and bone represent sources of mesenchymal stem cells (MSCs), but the number of MSCs from each has not been compared. Bone channeling may increase bone-derived MSC numbers participating in enthesis re-formation at the "footprint" repair site. The effect of preoperative channeling on increasing bone MSC numbers has never been reported. We asked (1) whether bone contains more MSCs than tendon at the time of arthroscopic repair and (2) whether bone preoperative channeling at the RC repair site increases the number of bone-derived MSCs at the time of surgery. METHODS: In 23 participants undergoing arthroscopic RC repair, bone was sampled from the footprint and tendon was sampled from the distal supraspinatus. We randomized participants to the channeling or no-channeling group 5 to 7 days before surgery. We enumerated MSCs from both tissues using the colony-forming unit-fibroblast (CFU-F) assay (10 per group). We identified MSC identity using flow cytometry and MSC tri-differentiation capacity (n = 3). RESULTS: Tendon CFU-F per gram exceeded bone CFU-F per gram for both groups (479 ± 173 CFU-F/g vs. 162 ± 54 CFU-F/g for channeling [P = .036] and 1334 ± 393 CFU-F/g vs. 284 ± 88 CFU-F/g for no channeling [P = .009]). Ninety-nine percent of cultured cells satisfied the MSC definition criteria. CONCLUSIONS: The distal supraspinatus tendon contained more MSCs per gram than the humeral footprint. Tendon may represent an important and overlooked MSC source for postoperative enthesis re-formation. Further studies are needed to evaluate the repair role of tendon MSCs and to recommend bone channeling in RC repair.

Effect of acute and chronic autophagy deficiency on skeletal muscle apoptotic signaling, morphology, and function.

Autophagy is a catabolic process that targets and degrades cytoplasmic materials. In skeletal muscle, autophagy is required for the control of mass under catabolic conditions, but is also basally active in the maintenance of myofiber homeostasis. In this study, we found that some specific autophagic markers (LC3-I, LC3-II, SQSTM1) were basally lower in glycolytic muscle compared to oxidative muscle of autophagy competent mice. In contrast, basal autophagic flux was higher in glycolytic muscle. In addition, we used several skeletal muscle-specific Atg7 transgenic mouse models to investigate the effect of acute (iAtg7-/-) and chronic (cAtg7-/-) autophagy deficiency on skeletal muscle morphology, contractility, and apoptotic signaling. While acute autophagy ablation (iAtg7-/-) resulted in increased centralized nuclei in glycolytic muscle, it did not alter contractile properties or measures of apoptosis and proteolysis. In contrast, with chronic autophagy deficiency (cAtg7-/-) there was an increased proportion of centralized nuclei, as well as reduced force and altered twitch kinetics in glycolytic muscle. Glycolytic muscle of cAtg7-/- mice also displayed an increased level of the pro-apoptotic protein BAX, as well as calpain and proteasomal enzymatic activity. Collectively, our data demonstrate cumulative damage from chronic skeletal muscle-specific autophagy deficiency with associated apoptotic and proteasomal upregulation. These findings point towards the importance of investigating different muscle/fiber types when studying skeletal muscle autophagy, and the critical role of autophagy in the maintenance of myofiber function, integrity, and cellular health.

Search for CP Violation in Neutrino and Antineutrino Oscillations by the T2K Experiment with 2.2×10

The T2K experiment measures muon neutrino disappearance and electron neutrino appearance in accelerator-produced neutrino and antineutrino beams. With an exposure of 14.7(7.6)×10^{20} protons on target in the neutrino (antineutrino) mode, 89 ν_{e} candidates and seven anti-ν_{e} candidates are observed, while 67.5 and 9.0 are expected for δ_{CP}=0 and normal mass ordering. The obtained 2σ confidence interval for the CP-violating phase, δ_{CP}, does not include the CP-conserving cases (δ_{CP}=0, π). The best-fit values of other parameters are sin^{2}θ_{23}=0.526_{-0.036}^{+0.032} and Δm_{32}^{2}=2.463_{-0.070}^{+0.071}×10^{-3} eV^{2}/c^{4}.

Folic acid supplementation during the preconception period: A systematic review and meta-analysis.

Guidelines recommend that women take folic acid supplements in the preconception period to prevent neural tube defects (NTDs) in their offspring. Estimates of adherence to this recommendation across different countries worldwide have not been synthesized. Medline, CINAHL, and EMBASE were systematically searched to identify studies reporting the prevalence of preconception folic acid supplementation. Pooled prevalence estimates for each country (where data were available) were calculated; and differences based on demographic, methodological, and study quality characteristics were examined. Of 3372 titles and abstracts screened, 722 full-texts were reviewed and 105 articles that reported 106 estimates of preconception folic acid supplementation in 34 countries were included. Pooled prevalence estimates were 32-51% in North America, 9-78% in Europe, 21-46% in Asia, 4-34% in the Middle East, 32-39% in Australia/New Zealand, and 0% in Africa. No South American studies were identified. Higher supplementation prevalence was observed in studies that had more highly educated samples, were conducted in fertility clinics, and assessed folic acid use via self-report. Of note, only 32% and 28% of studies reported timing of folic acid use and adherence to folic acid, respectively. Preconception folic acid supplementation is highly variable worldwide and many women may not achieve sufficient folate levels to prevent NTDs. To better understand non-adherence, recommendations for future research include: more explicit reporting of methodology, more detailed assessment of folic acid use, assessment of variables potentially relevant to folic acid use, and surveillance of folic acid use in a greater diversity of countries, especially in the developing world.

Shoe Lifts for Leg Length Discrepancy in Adults With Common Painful Musculoskeletal Conditions: A Systematic Review of the Literature.

OBJECTIVE: To determine whether shoe lifts effectively treat leg length discrepancy (LLD)-associated morbidities in adults with common painful musculoskeletal conditions. DATA SOURCES: Trip database, Cochrane Central Register of Controlled Trials database, PubMed database, Physiotherapy Evidence Database, and National Guideline Clearinghouse database. The search was performed in September 2017, was limited to English only, and had no time constraints. STUDY SELECTION: Two reviewers independently determined study eligibility. Inclusion criteria were (1) participants ≥18 years old with musculoskeletal-related complaints and LLD; (2) a shoe lift intervention was used; and (3) the study reported on pain, function, range of motion, patient satisfaction, quality of life, or adverse events. Randomized controlled trials (RCTs) and controlled intervention, cohort, before-and-after, case series, and case report studies were included. Three-hundred and nineteen articles were screened, and 9 guidelines were reviewed. DATA EXTRACTION: We extracted data pertaining to participant demographic characteristics, study setting, recruitment, randomization, method of LLD measurement, shoe lift characteristics, treatment duration, and outcome measures. We included 10 studies, including 1 RCT. DATA SYNTHESIS: LLD was associated with low back pain, scoliosis, and osteoarthritis of the hip and knee. Description of LLD correction strategy was often inadequate. Study quality was very low or poor. In non-RCT studies reporting on the proportion of participants who improved with a shoe lift, 88%±3% of 349 participants treated had partial or complete pain relief (effect size range, 66.7%-100%). All 22 RCT participants receiving treatment experienced pain relief (mean pain reduction, 27±9mm on a 150-mm visual analog scale). Two of 9 guidelines recommended shoe lift use based on consensus and were of moderate-to-high quality. CONCLUSIONS: There is low-quality evidence that shoe lifts reduce pain and improve function in patients with LLD and common painful musculoskeletal conditions. High-quality research evaluating a threshold LLD to correct and a strategy to do so is necessary. Developing an appropriate comparison group to test clinically relevant outcome measures would make a valuable contribution in this regard.

Ways of Knowing as a Framework for Developing Reflective Practice among Nursing Students.

Abstract Background:Nursing students face the challenge of developing a comprehensive understanding of the complex role of the registered nurse across various clinical settings. Frameworks such as the "ways of knowing", help students conceptualize and critically reflect upon important processes in their professional learning. However, the academic language used to describe frameworks can be challenging. PURPOSE: This manuscript has two purposes. First, to briefly describe the historical climate influencing the development of nursing as a discipline. Second, two clinical practicum scenarios in acute care and community-based care are explored with the application of Carper's four fundamental ways of knowing in nursing (empirical, aesthetic, self-knowledge, ethical), and Chinn and Kramer's fifth, emancipatory, knowing as foundational to developing reflexivity in clinical practice. CONCLUSION: These practical descriptions and concrete examples can assist students in incorporating the five ways of knowing into their reflective practice and thereby more fully develop their construct of nursing.

Combined Analysis of Neutrino and Antineutrino Oscillations at T2K.

T2K reports its first results in the search for CP violation in neutrino oscillations using appearance and disappearance channels for neutrino- and antineutrino-mode beams. The data include all runs from January 2010 to May 2016 and comprise 7.482×10^{20} protons on target in neutrino mode, which yielded in the far detector 32 e-like and 135 µ-like events, and 7.471×10^{20} protons on target in antineutrino mode, which yielded 4 e-like and 66 µ-like events. Reactor measurements of sin^{2}2θ_{13} have been used as an additional constraint. The one-dimensional confidence interval at 90% for the phase δ_{CP} spans the range (-3.13, -0.39) for normal mass ordering. The CP conservation hypothesis (δ_{CP}=0, π) is excluded at 90% C.L.

Nutrition and Cancer: An Historical Perspective.-The Past, Present, and Future of Nutrition and Cancer. Part 2. Misunderstanding and Ignoring Nutrition.

The role that nutrition plays in cancer development and treatment has received considerable attention in recent decades, but it still engenders considerable controversy. Within the cancer research and especially the clinical community, for example, nutritional factors are considered to play, at best, a secondary role. The role of nutrition in cancer development was noted by authorities as far back as the early 1800s, generally under the theory that cancer is "constitutional" in its origin, implying a complex, multifactorial, multistage etiology. Opponents of this idea insisted, rather vigorously, that cancer is a local unifactorial disease, best treated through surgery, with little attention paid to the etiology and possible prevention of cancer. This "local" theory, developed during the late 1700s and early 1800s, gradually included, in the late 1800s and early 1900s, chemotherapy and radiotherapy as treatment modalities, which now remain, along with surgery, as the basis of present-day cancer treatment. This highly reductionist paradigm left in its wake unfortunate consequences for the present day, which is the subject of this perspective.