Problem-Based Learning: Potential Application in a Hospital Setting

Background: Problem-Based Learning (PBL) has been incorporated into the curricula in many medical schools. It has also spread into schools of health sciences, nursing, public health, business and other professional education programs. The necessary for effective problem-based learning as well as the behavioral elements, which may be attributed to effective problem-based learning, are generally the characteristics that employers seek when making staffing decisions. This paper proposes that Problem-Based skills Learning is an appropriate adjunct to traditional staff development methods. Method: A group of volunteers (7) was solicited from the Respiratory Therapy staff at a University Hospital. The group participated in a PBL exercise. Upon completion of the PBL exercise the group was asked to complete a survey. The collected included: experience in the field and familiarity with education formats other than PBL. The group data was asked to compare PBL to other education formats. Positive and negative perceptions of PBL were noted. Results: 1he average professional experience of the group was 6.14 years with a range of 2.5 - 12 years in the hospital. The most preferred education format the lecture; the least preferred education format was the videotape. was The group had I 00% strong agreement with the statement indicating that PBL provided more opportunity for interaction with participants. There was also 100% strong agreement that PBL experiences should be incorporated into the department\u27s education plan. The group also strongly agreed (85.7%) that PBL was useful as a learning tool and relevant to clinical There was practice. slightly less enthusiastic response (57. l % and strong agreement 42.90/o agreement, as to the effectiveness other formats experienced. and enjoyment of PBL compared to Conclusions and Recommendations: Problem-Based Learning appears to be an acceptable methodology for professional continuing education and performance improvement in a hospital-based setting. The hospital-based PBL experience could be improved with careful planning to minimize interruptions and could be enhanced by incorporating web-based technology as a supplement between PBL sessions

Stroke-related Changes in Neuromuscular Fatigue of the Hip Flexors and Functional Implications

Objective: The aim of this study was to compare stroke-related changes in hip flexor neuromuscular fatigue of the paretic leg during a sustained isometric submaximal contraction with those of the nonparetic leg and controls and to correlate fatigue with clinical measures of function. Design: Hip torques were measured during a fatiguing hip flexion contraction at 20% of the hip flexion maximal voluntary contraction in the paretic and nonparetic legs of 13 people with chronic stroke and 10 age-matched controls. In addition, the participants with stroke performed a fatiguing contraction of the paretic leg at the absolute torque equivalent to 20% maximal voluntary contraction of the nonparetic leg and were tested for self-selected walking speed (10-m Walk Test) and balance (Berg). Results: When matching the nonparetic target torque, the paretic hip flexors had a shorter time to task failure compared with the nonparetic leg and controls (P \u3c 0.05). The time to failure of the paretic leg was inversely correlated with the reduction of hip flexion maximal voluntary contraction torque. Self-selected walking speed was correlated with declines in torque and steadiness. Berg-Balance scores were inversely correlated with the force fluctuation amplitude. Conclusions: Fatigue and precision of contraction are correlated with walking function and balance after stroke

Notch signaling controls chondrocyte hypertrophy via indirect regulation of Sox9

RBPjk-dependent Notch signaling regulates both the onset of chondrocyte hypertrophy and the progression to terminal chondrocyte maturation during endochondral ossification. It has been suggested that Notch signaling can regulate Sox9 transcription, although how this occurs at the molecular level in chondrocytes and whether this transcriptional regulation mediates Notch control of chondrocyte hypertrophy and cartilage development is unknown or controversial. Here we have provided conclusive genetic evidence linking RBPjk-dependent Notch signaling to the regulation of Sox9 expression and chondrocyte hypertrophy by examining tissue-specific Rbpjk mutant (Prx1Cre;Rbpjk(f/f)), Rbpjk mutant/Sox9 haploinsufficient (Prx1Cre;Rbpjk(f/f);Sox9(f/+)), and control embryos for alterations in SOX9 expression and chondrocyte hypertrophy during cartilage development. These studies demonstrate that Notch signaling regulates the onset of chondrocyte maturation in a SOX9-dependent manner, while Notch-mediated regulation of terminal chondrocyte maturation likely functions independently of SOX9. Furthermore, our in vitro molecular analyses of the Sox9 promoter and Notch-mediated regulation of Sox9 gene expression in chondrogenic cells identified the ability of Notch to induce Sox9 expression directly in the acute setting, but suppresses Sox9 transcription with prolonged Notch signaling that requires protein synthesis of secondary effectors

Lyman Continuum Escape Fraction of Star-forming Dwarf Galaxies at z ~ 1

To date, no direct detection of Lyman continuum emission has been measured for intermediate-redshift (z ~ 1) star-forming galaxies. We combine Hubble Space Telescope grism spectroscopy with GALEX UV and ground-based optical imaging to extend the search for escaping Lyman continuum to a large (~600) sample of z ~ 1 low-mass log(M)≃ 9.3 M_☉), moderately star-forming (ψ ≾ 10M_☉ yr^(−1)) galaxies selected initially on Hα emission. The characteristic escape fraction of LyC from star-forming galaxies (SFGs) that populate this parameter space remains weakly constrained by previous surveys, but these faint (sub-Lsstarf) SFGs are assumed to play a significant role in the reionization of neutral hydrogen in the intergalactic medium (IGM) at high redshift z > 6. We do not make an unambiguous detection of escaping LyC radiation from this z ~ 1 sample, individual non-detections to constrain the absolute Lyman continuum escape fraction, f_(esc) 200Å), which are thought to be close analogs of high redshift sources of reionization. For reference, we also present an emissivity-weighted escape fraction that is useful for measuring the general contribution SFGs to the ionizing UV background. In the discussion, we consider the implications of these intermediate redshift constraints for the reionization of hydrogen in the IGM at high (z > 6) redshift. If we assume our z ~ 1 SFGs, for which we measure this emissivity-weighted f_(esc), are analogs to the high redshift sources of reionization, we find it is difficult to reconcile reionization by faint (M}_(UV) ≾-13) SFGs with a low escape fraction (f_(esc) < 3%), with constraints from independent high redshift observations. If f_(esc) evolves with redshift, reionization by SFGs may be consistent with observations from Planck

The mass-metallicity relation at z~1-2 and its dependence on star formation rate

We present a new measurement of the gas-phase mass-metallicity relation (MZR), and its dependence on star formation rates (SFRs) at 1.3 < z < 2.3. Our sample comprises 1056 galaxies with a mean redshift of z = 1.9, identified from the Hubble Space Telescope Wide Field Camera 3 (WFC3) grism spectroscopy in the Cosmic Assembly Near-Infrared Deep Extragalactic Survey (CANDELS) and the WFC3 Infrared Spectroscopic Parallel Survey (WISP). This sample is four times larger than previous metallicity surveys at z ~ 2, and reaches an order of magnitude lower in stellar mass (10^8 M_sun). Using stacked spectra, we find that the MZR evolves by 0.3 dex relative to z ~ 0.1. Additionally, we identify a subset of 49 galaxies with high signal-to-noise (SNR) spectra and redshifts between 1.3 < z < 1.5, where H-alpha emission is observed along with [OIII] and [OII]. With accurate measurements of SFR in these objects, we confirm the existence of a mass-metallicity-SFR (M-Z-SFR) relation at high redshifts. These galaxies show systematic differences from the local M-Z-SFR relation, which vary depending on the adopted measurement of the local relation. However, it remains difficult to ascertain whether these differences could be due to redshift evolution, as the local M-Z-SFR relation is poorly constrained at the masses and SFRs of our sample. Lastly, we reproduced our sample selection in the IllustrisTNG hydrodynamical simulation, demonstrating that our line flux limit lowers the normalization of the simulated MZR by 0.2 dex. We show that the M-Z-SFR relation in IllustrisTNG has an SFR dependence that is too steep by a factor of around three.Comment: Accepted for publication in ApJ; 41 pages, 20 figure

Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma

Background: Uveal melanoma is a disease that is distinct from cutaneous melanoma, with a low tumor mutational burden and a 1-year overall survival of approximately 50% in patients with metastatic uveal melanoma. Data showing a proven overall survival benefit with a systemic treatment are lacking. Tebentafusp is a bispecific protein consisting of an affinity-enhanced T-cell receptor fused to an anti-CD3 effector that can redirect T cells to target glycoprotein 100-positive cells. Methods: In this open-label, phase 3 trial, we randomly assigned previously untreated HLA-A*02:01-positive patients with metastatic uveal melanoma in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator's choice of therapy with single-agent pembrolizumab, ipilimumab, or dacarbazine (control group), stratified according to the lactate dehydrogenase level. The primary end point was overall survival. Results: A total of 378 patients were randomly assigned to either the tebentafusp group (252 patients) or the control group (126 patients). Overall survival at 1 year was 73% in the tebentafusp group and 59% in the control group (hazard ratio for death, 0.51; 95% confidence interval [CI], 0.37 to 0.71; P<0.001) in the intention-to-treat population. Progression-free survival was also significantly higher in the tebentafusp group than in the control group (31% vs. 19% at 6 months; hazard ratio for disease progression or death, 0.73; 95% CI, 0.58 to 0.94; P = 0.01). The most common treatment-related adverse events in the tebentafusp group were cytokine-mediated events (due to T-cell activation) and skin-related events (due to glycoprotein 100-positive melanocytes), including rash (83%), pyrexia (76%), and pruritus (69%). These adverse events decreased in incidence and severity after the first three or four doses and infrequently led to discontinuation of the trial treatment (2%). No treatment-related deaths were reported. Conclusions: Treatment with tebentafusp resulted in longer overall survival than the control therapy among previously untreated patients with metastatic uveal melanoma. (Funded by Immunocore; ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.). Copyright © 2021 Massachusetts Medical Society

Clinical Outcomes and Patient-Matched Molecular Composition of Relapsed Medulloblastoma

PURPOSE We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors. METHODS Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing. RESULTS A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup divergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving MYC, MYCN, and FBXW7. Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms. CONCLUSION Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular targets and identification of occult secondary malignancies

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

The unfolded protein response governs integrity of the haematopoietic stem-cell pool during stress.

The blood system is sustained by a pool of haematopoietic stem cells (HSCs) that are long-lived due to their capacity for self-renewal. A consequence of longevity is exposure to stress stimuli including reactive oxygen species (ROS), nutrient fluctuation and DNA damage. Damage that occurs within stressed HSCs must be tightly controlled to prevent either loss of function or the clonal persistence of oncogenic mutations that increase the risk of leukaemogenesis. Despite the importance of maintaining cell integrity throughout life, how the HSC pool achieves this and how individual HSCs respond to stress remain poorly understood. Many sources of stress cause misfolded protein accumulation in the endoplasmic reticulum (ER), and subsequent activation of the unfolded protein response (UPR) enables the cell to either resolve stress or initiate apoptosis. Here we show that human HSCs are predisposed to apoptosis through strong activation of the PERK branch of the UPR after ER stress, whereas closely related progenitors exhibit an adaptive response leading to their survival. Enhanced ER protein folding by overexpression of the co-chaperone ERDJ4 (also called DNAJB9) increases HSC repopulation capacity in xenograft assays, linking the UPR to HSC function. Because the UPR is a focal point where different sources of stress converge, our study provides a framework for understanding how stress signalling is coordinated within tissue hierarchies and integrated with stemness. Broadly, these findings reveal that the HSC pool maintains clonal integrity by clearance of individual HSCs after stress to prevent propagation of damaged stem cells