Miracle-dz/UniFAR-FTUs huggingface dataset:
The Combination of ISCOMATRIX Adjuvant and TLR Agonists Induces Regression of Established Solid Tumors In Vivo

The development of therapeutic vaccines for treatment of established cancer has proven challenging. Cancer vaccines not only need to induce a robust tumor Ag-specific immune response but also need to overcome the tolerogenic and immunosuppressive microenvironments that exist within many solid cancers. ISCOMATRIX adjuvant (ISCOMATRIX) is able to induce both tumor Ag-specific cellular and Ab responses to protect mice against tumor challenge, but this is insufficient to result in regression of established solid tumors. In the current study, we have used B16-OVA melanoma, Panc-OVA pancreatic, and TRAMP-C1 prostate cancer mouse tumor models to test therapeutic efficacy of ISCOMATRIX vaccines combined with other immune modulators. The coadministration of an ISCOMATRIX vaccine with the TLR3 agonist, polyinosinic-polycytidylic acid, and TLR9 agonist, CpG, reduced tumor growth in all tumor models and the presence of ISCOMATRIX in the formulation was critical for the therapeutic efficacy of the vaccine. This vaccine combination induced a robust and multifunctional CD8+ T cell response. Therapeutic protection required IFN-γ and CD8+ T cells, whereas NK and CD4+ T cells were found to be redundant. ISCOMATRIX vaccines combined with TLR3 and TLR9 agonists represent a promising cancer immunotherapy strategy.
The educational theory basis of team-based learning

Background: Health care providers require the ability to use critical thinking skills and work effectively in a team as a part of an overall set of competencies. Therefore, educational programs should use appropriate methods based in educational theory to effectively graduate learners with these abilities. Team-based learning (TBL) is a method that has been introduced in healthcare education to foster critical thinking skills while students work in high functioning teams. Aims: This article will show how TBL follows the principles of constructivist learning theory. Method: The principles of constructivist learning theory are discussed in relation to the teaching method of team-based learning. The effectiveness of TBL in healthcare education is then reviewed. Results: TBL is learner centered with the teacher acting as an expert facilitator and also provides students with opportunities to expose inconsistencies between their current understandings and new experiences thus stimulating development of new personal mental frameworks built upon previous knowledge. The learning is active using relevant problems and group interaction. Teamwork skills are strengthened by focused reflection on new experiences during the group sessions and on teamwork success by providing feedback to group members. Conclusion: Since these aspects are all essential components of constructivist educational theory, TBL is solidly grounded in the theory and is a promising method to strengthen healthcare education.
Views From Within and Beyond: Illness Narratives of African-American Men With Type 2 Diabetes

In Brief The management and impact of type 2 diabetes on the sense of self, lifestyle, and significant others of African-American men is not well understood. This article reports on a study to examine perceptions of managing and coping with diabetes among African-American men and summarizes its findings regarding the distribution of clinical biomarkers, participants9 perceptions of the cause of their diabetes, its impact on masculinity, use of home remedies for diabetes care, and the degree to which effective coping skills and social support are engaged and available.
A cross sectional study of socio-demographic determinants of anaemia in adolesecent boys of urban slum area in South India -

Background: Adolescence a period of transition between childhood and adulthood is a significant period of human growth and maturation. The term “adolescence” has been defined by WHO as those including between 10 to 19 years. During this period, more than 20% of the total growth in stature and 50% of adult bone mass are achieved and iron requirement increases dramatically in both adolescent boys and girls. Available literature from India confirms that anaemia is common among adolescent girls but there is a paucity of information on status of anaemia among adolescent boys and most of the studies are based on school – going population and are not from the community. Materials and methods: The present cross-sectional study was conducted in 440 Adolescent boys aged 10 to 19 years residing in the registered families in the urban slum area of Andhra Pradesh. Results: The prevalence of anemia in adolescent boys aged 10 to 19 years were found to be 36.14%. The various sociodemographic determinants which were found to be statistically significant in boys includes type of family , socioeconomic status, adolescents educational status, H/o of malaria infection, habit of taking meal. Conclusion: Iron supplements have to be provided to the adolescent boys also as in our country, most of the National programmes related to supplementary nutrition are focusing only on adolescent girls, but none of the programmes include adolescent boys.
IgM and IgA Rheumatoid Factors Purified from Rheumatoid Arthritis Sera Boost the Fc Receptor– and Complement-Dependent Effector Functions of the Disease-Specific Anti–Citrullinated Protein Autoantibodies

Rheumatoid factors (RF) and the disease-specific anti–citrullinated protein autoantibodies (ACPA) coexist in the joints of rheumatoid arthritis (RA) patients where they probably contribute to synovitis. We investigated the influence of IgM and IgA RF on the FcR- and complement-dependent effects of ACPA immune complexes (ACPA-IC). When stimulated by ACPA-IC formed in the presence of IgM RF or IgA RF fractions purified from RA serum pools, M-CSF–generated macrophages skewed their cytokine response toward inflammation, with increases in the TNF-α/IL-10 ratio and in IL-6 and IL-8 secretion, and decreases in the IL-1Ra/IL-1β ratio. In the IgM RF-mediated amplification of the inflammatory response of macrophages, the participation of an IgM receptor was excluded, notably by showing that they did not express any established receptor for IgM. Rather, this amplification depended on the IgM RF-mediated recruitment of more IgG into the ACPA-IC. However, the macrophages expressed FcαRI and blocking its interaction with IgA inhibited the IgA RF-mediated amplification of TNF-α secretion induced by ACPA-IC, showing its major implication in the effects of RF of the IgA class. LPS further amplified the TNF-α response of macrophages to RF-containing ACPA-IC. Lastly, the presence of IgM or IgA RF increased the capacity of ACPA-IC to activate the complement cascade. Therefore, specifically using autoantibodies from RA patients, the strong FcR-mediated or complement-dependent pathogenic potential of IC including both ACPA and IgM or IgA RF was established. Simultaneous FcR triggering by these RF-containing ACPA-IC and TLR4 ligation possibly makes a major contribution to RA synovitis.
C-Type Lectin Receptor MCL Facilitates Mincle Expression and Signaling through Complex Formation

C-type lectin receptors expressed in APCs are recently defined pattern recognition receptors that play a crucial role in immune responses against pathogen-associated molecular patterns. Among pathogen-associated molecular patterns, cord factor (trehalose-6,6′-dimycolate [TDM]) is the most potent immunostimulatory component of the mycobacterial cell wall. Two C-type lectin receptors, macrophage-inducible C-type lectin (Mincle) and macrophage C-type lectin (MCL), are required for immune responses against TDM. Previous studies indicate that MCL is required for TDM-induced Mincle expression. However, the mechanism by which MCL induces Mincle expression has not been fully understood. In this study, we demonstrate that MCL interacts with Mincle to promote its surface expression. After LPS or zymosan stimulation, MCL-deficient bone marrow–derived dendritic cells (BMDCs) had a lower level of Mincle protein expression, although mRNA expression was comparable with wild-type BMDCs. Meanwhile, BMDCs from MCL transgenic mice showed an enhanced level of Mincle expression on the cell surface. MCL was associated with Mincle through the stalk region and this region was necessary and sufficient for the enhancement of Mincle expression. This interaction appeared to be mediated by the hydrophobic repeat of MCL, as substitution of four hydrophobic residues within the stalk region with serine (MCL4S) abolished the function to enhance the surface expression of Mincle. MCL4S mutant failed to restore the defective TDM responses in MCL-deficient BMDCs. These results suggest that MCL positively regulates Mincle expression through protein–protein interaction via its stalk region, thereby magnifying Mincle-mediated signaling.
Definition of Proteasomal Peptide Splicing Rules for High-Efficiency Spliced Peptide Presentation by MHC Class I Molecules

Peptide splicing, in which two distant parts of a protein are excised and then ligated to form a novel peptide, can generate unique MHC class I–restricted responses. Because these peptides are not genetically encoded and the rules behind proteasomal splicing are unknown, it is difficult to predict these spliced Ags. In the current study, small libraries of short peptides were used to identify amino acid sequences that affect the efficiency of this transpeptidation process. We observed that splicing does not occur at random, neither in terms of the amino acid sequences nor through random splicing of peptides from different sources. In contrast, splicing followed distinct rules that we deduced and validated both in vitro and in cells. Peptide ligation was quantified using a model peptide and demonstrated to occur with up to 30% ligation efficiency in vitro, provided that optimal structural requirements for ligation were met by both ligating partners. In addition, many splicing products could be formed from a single protein. Our splicing rules will facilitate prediction and detection of new spliced Ags to expand the peptidome presented by MHC class I Ags.
Clerkships do not improve recognition of patient hazards by advanced medical students during chart review

Patient safety has been receiving increasingly more attention in the last two decades. However, research on patient safety issues during medical school training is scarce. Some patterns of patient hazards (especially diagnostic errors, medication errors, nosocomial infections) constitute a large fraction of patient hazards. Chart review by specially trained physicians is the gold standard for identification of some of these common patient hazards. Thus, a routine screening for common patient hazards during ward rounds might improve patient safety. Since chart review is not commonly taught in most medical schools, we investigated whether advanced medical students acquire the skill to identify patient hazards during chart review en passant (in passing) during clerkships. A total of 128 fifth-year medical students were asked to review fictional standardized patient charts with 12 common patient hazards. The students’ notes were rated by two blinded raters using a checklist. We asked the students how many weeks they had spent in clerkships in various specialties, particularly internal medicine, surgery and general medicine. The students reported to have spent 11 4 weeks in clerkships so far. In our study, the students identified only 17%, IQR1⁄4 8–30% of the patient hazards. There was no significant correlation between the number of weeks spent in clerkships and identified patient hazards. Only students who reported to have completed at least one chart review previously on their own (n1⁄4 13, 10.2% of our study sample) identified more patient hazards than students who had never completed a chart review (29%, IQR1⁄4 19–43% versus 17%, IQR1⁄4 8–25%, p1⁄4 0.02). It is unclear, whether these students improved their recognition of patient hazards during the clerkship or whether the students who perform chart review during clerkships constitute a different sample compared to students who do not perform chart review. We therefore conclude that unstructured clerkships do not contribute significantly to identification of patient hazards by advanced medical students during chart review. A specific training may be warranted.
Comparison of three problem-based learning conditions (real patients, digital and paper) with lecture-based learning in a dermatology course: A prospective randomized study from China

Background: The precise effect and the quality of different cases used in dermatology problem-based learning (PBL) curricula are yet unclear. Aim: To prospectively compare the impact of real patients, digital, paper PBL (PPBL) and traditional lecture-based learning (LBL) on academic results and student perceptions. Methods: A total of 120 students were randomly allocated into either real-patients PBL (RPBL) group studied via real-patient cases, digital PBL (DPBL) group studied via digital-form cases, PPBL group studied via paper-form cases, or conventional group who received didactic lectures. Academic results were assessed through review of written examination, objective structured clinical examination and student performance scores. A five-point Likert scale questionnaire was used to evaluate student perceptions. Results: Compared to those receiving lectures only, all PBL participants had better results for written examination, clinical examination and overall performance. Students in RPBL group exhibited better overall performance than those in the other two PBL groups. Real-patient cases were more effective in helping develop students’ self-directed learning skills, improving their confidence in future patient encounters and encouraging them to learn more about the discussed condition, compared to digital and paper cases. Conclusion: Both real patient and digital triggers are helpful in improving students’ clinical problem-handling skills. However, real patients provide greater benefits to students.
Negative Regulation of Memory Phenotype CD8 T Cell Conversion by Adhesion and Degranulation–Promoting Adapter Protein

The maintenance of T cell repertoire diversity involves the entry of newly developed T cells, as well as the maintenance of memory T cells generated from previous infections. This balance depends on competition for a limited amount of homeostatic cytokines and interaction with self-peptide MHC class I. In the absence of prior infection, memory-like or memory phenotype (MP) CD8 T cells can arise from homeostatic cytokine exposure during neonatal lymphopenia. Aside from downstream cytokine signaling, little is known about the regulation of the conversion of naive CD8 T cells to MP CD8 T cells during acute lymphopenia. We have identified a novel negative regulatory role for adhesion and degranulation–promoting adapter protein (ADAP) in CD8 T cell function. We show that in the absence of ADAP, naive CD8 T cells exhibit a diminished response to stimulatory Ag, but an enhanced response to weak agonist-altered peptide ligands. ADAP-deficient mice exhibit more MP CD8 T cells that occur following thymic emigration and are largely T cell intrinsic. Naive ADAP-deficient CD8 T cells are hyperresponsive to lymphopenia in vivo and exhibit enhanced activation of STAT5 and homeostatic Ag-independent proliferation in response to IL-15. Our results indicate that ADAP dampens naive CD8 T cell responses to lymphopenia and IL-15, and they demonstrate a novel Ag-independent function for ADAP in the suppression of MP CD8 T cell generation.
Psychiatric problems of detainees under the Anti-Terrorism Crime and Security Act 2001

AIMS AND METHOD To provide a composite view of the impact of indefinite detention under the Anti-Terrorism Crime and Security Act 2001. Until recently, a number of detainees had been detained under this legislation since December 2001. The impact of this on eight detainees and three of their spouses is examined through qualitative analysis of 48 reports and documents compiled by 11 psychiatrists and 1 psychologist. RESULTS Detention has had a severe adverse impact on the mental health of all detainees and the spouses interviewed. All were clinically depressed and a number had post-traumatic stress disorder. The indefinite nature of detention was a major factor in their deterioration. CLINICAL IMPLICATIONS The use of indefinite detention without trial has severe adverse consequences that may pose insurmountable problems for the prison healthcare system.
Anti–Factor H Autoantibodies in C3 Glomerulopathies and in Atypical Hemolytic Uremic Syndrome: One Target, Two Diseases

Autoantibodies targeting factor H (FH), which is a main alternative complement pathway regulatory protein, have been well characterized in atypical hemolytic uremic syndrome (aHUS) but have been less well described in association with alternative pathway–mediated glomerulopathies (GP). In this study, we studied 17 patients presenting with GP who were positive for anti-FH IgG. Clinical data were collected and biological characteristics were compared with those of patients presenting with anti-FH Ab-associated aHUS. In contrast to the aHUS patients, the GP patients had no circulating FH-containing immune complexes, and their anti-FH IgG had a weaker affinity for FH. Functional studies demonstrated that these Abs induced no perturbations in FH cell surface protection or the binding of FH to its ligand. However, anti-FH IgG samples isolated from three patients were able to affect the factor I cofactor activity of FH. Epitope mapping identified the N-terminal domain of FH as the major binding site for GP patient IgG. No homozygous deletions of the CFHR1 and CFHR3 genes, which are frequently associated with the anti-FH Ab in aHUS patients, were found in the GP patients. Finally, anti-FH Abs were frequently associated with the presence of C3 nephritic factor in child GP patients and with monoclonal gammopathy in adult GP patients, who frequently showed Ig Lchain restriction during reactivity against factor H. These data provide deeper insights into the pathophysiological differences between aHUS and GP, demonstrating heterogeneity of anti-FH IgG.
Mechanical diagnosis and therapy in back pain: Compliance and social cognitive theory

The aim of this study was to describe social cognitive theory (SCT) constructs and exercise compliance, and to explore relations between SCT variables and exercise compliance in patients with lumbar derangement syndrome during mechanical diagnosis and therapy (MDT) treatment. Fifty-eight subjects completed the study. The data collection included measures relevant to SCT constructs and compliance: outcome expectations and expectancies, self-efficacy expectations, behavioural capability, and self-reported frequency of exercise occasions, as well as treatment outcomes regarding pain intensity and disability. Data were collected at five occasions during treatment and during a 2-month follow-up period. The subjects received a mean of three movements (range one to five) as home exercises. The mean number of weeks with these exercises was 4 (range 1–6). High median scores were found in all variables related to SCT. The median compliance rates varied between 79% (week 1) and 91% (week 3) during treatment. During the first follow-up month, the compliance rate was 79% and during the second month of follow-up 62%. Pain intensity and disability decreased during treatment. Although there were no significant correlations between the SCT variables and exercise compliance, the descriptive data are in line with SCT.
A six step approach for developing computer based assessment in medical education

Assessment, which entails the systematic evaluation of student learning, is an integral part of any educational process. Computer-based assessment (CBA) techniques provide a valuable resource to students seeking to evaluate their academic progress through instantaneous, personalized feedback. CBA reduces examination, grading and reviewing workloads and facilitates training. This paper describes a six step approach for developing CBA in higher education and evaluates student perceptions of computer-based summative assessment at the College of Medicine, King Abdulaziz University. A set of questionnaires were distributed to 341 third year medical students (161 female and 180 male) immediately after examinations in order to assess the adequacy of the system for the exam program. The respondents expressed high satisfaction with the first Saudi experience of CBA for final examinations. However, about 50% of them preferred the use of a pilot CBA before its formal application; hence, many did not recommend its use for future examinations. Both male and female respondents reported that the range of advantages offered by CBA outweighed any disadvantages. Further studies are required to monitor the extended employment of CBA technology for larger classes and for a variety of subjects at universities.
The DNA Ligase IV Syndrome R278H Mutation Impairs B Lymphopoiesis via Error-Prone Nonhomologous End-Joining

Hypomorphic mutations in the nonhomologous end-joining (NHEJ) DNA repair protein DNA ligase IV (LIG4) lead to immunodeficiency with varying severity. In this study, using a murine knock-in model, we investigated the mechanisms underlying abnormalities in class switch recombination (CSR) associated with the human homozygous Lig4 R278H mutation. Previously, we found that despite the near absence of Lig4 end-ligation activity and severely reduced mature B cell numbers, Lig4R278H/R278H (Lig4R/R) mice exhibit only a partial CSR block, producing near normal IgG1 and IgE but substantially reduced IgG3, IgG2b, and IgA serum levels. In this study, to address the cause of these abnormalities, we assayed CSR in Lig4R/R B cells generated via preassembled IgH and IgK V region exons (HL). This revealed that Lig4R278H protein levels while intact exhibited a higher turnover rate during activation of switching to IgG3 and IgG2b, as well as delays in CSR kinetics associated with defective proliferation during activation of switching to IgG1 and IgE. Activated Lig4R/RHL B cells consistently accumulated high frequencies of activation-induced cytidine deaminase–dependent IgH locus chromosomal breaks and translocations and were more prone to apoptosis, effects that appeared to be p53-independent, as p53 deficiency did not markedly influence these events. Importantly, NHEJ instead of alternative end-joining (A-EJ) was revealed as the predominant mechanism catalyzing robust CSR. Defective CSR was linked to failed NHEJ and residual A-EJ access to unrepaired double-strand breaks. These data firmly demonstrate that Lig4R278H activity renders NHEJ to be more error-prone, and they predict increased error-prone NHEJ activity and A-EJ suppression as the cause of the defective B lymphopoiesis in Lig4 patients.