Miracle-dz/UniFAR-FTUs huggingface dataset:
Women in Academic Medicine: Measuring Stereotype Threat Among Junior Faculty.

BACKGROUND Gender stereotypes in science impede supportive environments for women. Research suggests that women's perceptions of these environments are influenced by stereotype threat (ST): anxiety faced in situations where one may be evaluated using negative stereotypes. This study developed and tested ST metrics for first time use with junior faculty in academic medicine. METHODS Under a 2012 National Institutes of Health Pathfinder Award, Stanford School of Medicine's Office of Diversity and Leadership, working with experienced clinicians, social scientists, and epidemiologists, developed and administered ST measures to a representative group of junior faculty. RESULTS 174 School of Medicine junior faculty were recruited (62% women, 38% men; 75% assistant professors, 25% instructors; 50% white, 40% Asian, 10% underrepresented minority). Women reported greater susceptibility to ST than did men across all items including ST vulnerability (p < 0.001); rejection sensitivity (p = 0.001); gender identification (p < 0.001); perceptions of relative potential (p = 0.048); and, sense of belonging (p = 0.049). Results of career-related consequences of ST were more nuanced. Compared with men, women reported lower beliefs in advancement (p = 0.021); however, they had similar career interest and identification, felt just as connected to colleagues, and were equally likely to pursue careers outside academia (all p > 0.42). CONCLUSIONS Innovative ST metrics can provide a more complete picture of academic medical center environments. While junior women faculty are susceptible to ST, they may not yet experience all of its consequences in their early careers. As such, ST metrics offer a tool for evaluating institutional initiatives to increase supportive environments for women in academic medicine.
Block of native Ca(2+)‐permeable AMPA receptors in rat brain by intracellular polyamines generates double rectification.

1. The influence of intracellular factors on current rectification of different subtypes of native alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazoleproprionate receptors (AMPARs) was studied in rat brain slices by combining fast application of glutamate with patch pipette perfusion. 2. The peak current‐voltage (I‐V) relation of the AMPARs expressed in Bergmann glial cells of cerebellum and dentate gyrus (DG) basket cells of hippocampus was weakly rectifying in outside‐out patches and nystatin‐perforated vesicles, but showed a doubly rectifying shape with a region of reduced slope between 0 and +40 mV in nucleated patches. The I‐V relation of AMPARs expressed in hippocampal CA3 pyramidal neurones was linear in all recording configurations. 3. Intracellular application of 25 microM spermine, a naturally occurring polyamine, blocked outward currents in outside‐out patches from Bergmann glial cells and DG basket cells in a voltage‐dependent manner, generating I‐V relations with a doubly rectifying shape which were similar to those recorded in nucleated patches. AMPARs in CA3 pyramidal cell patches were unaffected by 25 microM spermine. 4. The half‐maximal blocking concentration of spermine at +40 mV was 0.3 microM in Bergmann glial cell patches and 1.5 microM in DG basket cell patches, whereas it was much higher (>> 100 microM) for CA3 pyramidal cell patches. Spermidine also affected current rectification, but with lower affinity. The block of outward current by polyamines following voltage jumps developed within < 0.5 ms. 5. We conclude that current rectification, rather than being an intrinsic property of the Ca(2+)‐permeable AMPAR channel, is generated by polyamine block.
User Acceptability and Feasibility of Self-Testing With HIV Rapid Tests

Objective:Because HIV rapid tests are considered for self-testing, this study aims to determine the user acceptability and feasibility of self-testing. Methods:A cross-sectional study was performed on 350 systematically sampled participants across 2 Singapore HIV testing centers using the Abbott Determine HIV 1/2 blood sample rapid test (Abbott Laboratories, Abbott Park, IL). Participants were surveyed on knowledge of and attitudes toward rapid testing. To determine interrater agreement between self-testing and trained personnel testing, participants performed self-testing with visual instructions, followed by trained personnel testing. Ability to identify test outcomes was determined through interpretation of sample test results. Results:Eighty-nine percent of participants preferred testing in private, but most indicated that confidential counseling by trained counselors was necessary. Almost 90% found the kit easy to use and instructions easy to understand. Nevertheless, 85% failed to perform all steps correctly, especially blood sampling, and 56% had invalid results because of incorrect test performance. Interrater agreement between results from self-testing and trained personnel testing had a κ value of 0.28. Twelve percent could not correctly determine results using sample tests, including 2% and 7% who read positive and negative samples, respectively, incorrectly. Conclusions:A substantial proportion could not perform self-testing or identify outcomes. Self-testing with the Determine HIV 1/2 kit in Singapore should be deferred.
Subclinical reduction in left ventricular function using triplane and 2D speckle tracking echocardiography after anthracycline exposure in children

Objective: Speckle tracking echocardiography (STE) enables global and regional evaluation of the left ventricle (LV); therefore, it is the most useful method for detecting subclinical dysfunction in patients exposed to cardiotoxic agents. A novel technique triplane (3P) echocardiography also allows single beat assessment of LV global longitudinal strain values. We firstly aimed to demonstrate both two-dimensional (2D)- and 3P-STE-derived LV global longitudinal strain measurements in children after anthracycline exposure. Methods: This study included 23 cross-sectionally enrolled asymptomatic pediatric cancer patients who received anthracycline chemotherapy and 17 healthy controls matched by age, gender, and body surface area. All subjects underwent detailed 2D, Doppler, 2D-STE, and 3P-STE for assessment of LV function. The patients had received a median cumulative dose of 150 mg/m2. Results: 1. From “Pulsed” Doppler-based measurements, only pulmonary vein flow ratio showed a significant difference between the groups. 2. When measurements were taken from the interventricular septum, the patients’ ejection time values decreased significantly and their myocardial performance index values increased significantly; when the measurements were taken from the LV free wall, the peak systolic velocities showed a statistically significant difference. 3. Both 2D- and 3P-STE-derived longitudinal myocardial deformation values of LV were lower in the patient group. 4. 2D-STE-derived LV circumferential strain values were decreased in the patient group, whereas radial strain values were not significantly different compared with matched controls. Conclusion: Using Doppler and 2D- and 3P-STE methods, this study confirmed the subclinical LV dysfunction in patients after anthracycline exposure.
Prevalence of CYP2C19 alleles, pharmacokinetic and pharmacodynamic variation of clopidogrel and prasugrel in Bangladeshi population

The extent to which cytochrome P450 (CYP) 2C19 genotype influences the effectiveness of clopidogrel remains uncertain due to considerable heterogeneity between studies. We used the polymerase chain reaction restriction fragment length polymorphism (PCR‐RFLP) method for genotyping loss of function (LOF) allele, CYP2C19*2 and gain of function (GOF) allele, CYP2C19*17 in 163 patients undergoing PCI and 165 healthy volunteers from an ethnically distinctive Bangladeshi population. Thirty‐eight patients took prasugrel and 125 patients took clopidogrel among whom 30 patients had their clopidogrel active metabolites (CAM) determined by LC‐MS/MS 1–1.5 h after clopidogrel intake. All patients who underwent PCI had their P2Y12 per cent inhibition (PRI) measured by VerifyNow System. The impact of different genotypes on CAM and PRI were also determined. We did not find significant variation of CYP2C19*2 (P > 0.05) and CYP2C9*17 (P > 0.05) alleles among healthy volunteers and patients. CAM concentration as well as PRI by clopidogrel varied significantly (P < 0.05) based on genotypic variation of CYP2C19*2 and CYP2C19*17 individually. Such influence was not observed in case of prasugrel. Genotypic variation did not impact PRI but as a whole PRI by prasugrel was better than that of clopidogrel (P < 0.05). Due to presence of both of alleles the effect on PRI by clopidogrel could not be predicted, effectively indicating possible involvement of other factors. Genotype guided clopidogrel dose adjustment would be beneficial and therefore we propose mandatory genotyping before clopidogrel dosing. Prasugrel proved to be less affected by genotypic variability, but due to lack of sufficient long‐term toxicity data, caution would be adopted before substituting clopidogrel.
High Doses of OP-1 Inhibit Fibrous Tissue Ingrowth in Impaction Grafting

A major concern in using growth factors in impaction grafting is the potential stimulation of the osteoclastic lineage. A solution would be using an osteoconductive material resistant to resorption and providing initial stability after reconstruction. Growth factors may promote bone formation in combination with such graft materials. We determined whether OP-1 would promote the incorporation of impacted morselized allografts and tricalcium phosphate/ hydroxyapatite (TCP/HA) into host bone, whether bone formation would be preceded by an initial process of accelerated resorption, and whether the response to OP-1 remodeling/incorporation would be dose-related. We performed two bone chamber studies in goats to ascertain the early effects of OP-1 dose on resorption and incorporation of impacted morselized allografts and TCP/HA. After 4 weeks, the incorporation process of impacted morselized allografts and TCP/HA was not promoted by OP-1. We observed no signs of accelerated resorption preceding bone formation. An increase in OP-1 dose resulted in an inhibition of fibrous tissue formation but OP-1 did not promote bone formation. Early failures in impaction grafting, using mixes with OP-1, might be explained by the lack of fibrous tissue ingrowth and not by increased resorption and remodeling.
Soluble, high-affinity dimers of T-cell receptors and class II major histocompatibility complexes: biochemical probes for analysis and modulation of immune responses.

T cell receptors (TCR) and major histocompatibility complex (MHC) molecules are integral membrane proteins that have central roles in cell-mediated immune recognition. Therefore, soluble analogs of these molecules would be useful for analyzing and possibly modulating antigen-specific immune responses. However, due to the intrinsic low-affinity and inherent solubility problems, it has been difficult to produce soluble high-affinity analogs of TCR and class II MHC molecules. This report describes a general approach which solves this intrinsic low-affinity by constructing soluble divalent analogs using IgG as a molecular scaffold. The divalent nature of the complexes increases the avidity of the chimeric molecules for cognate ligands. The generality of this approach was studied by making soluble divalent analogs of two different classes of proteins, a TCR (2C TCR2Ig) and a class II MHC (MCCI-Ek2Ig) molecule. Direct flow cytometry assays demonstrate that the divalent 2C TCR2Ig chimera retained the specificity of the native 2C TCR, while displaying increased avidity for cognate peptide/MHC ligands, resulting in a high-affinity probe capable of detecting interactions that heretofore have only been detected using surface plasmon resonance. TCR2IgG was also used in immunofluorescence studies to show ER localization of intracellular peptide-MHC complexes after peptide feeding. MCCI-Ek2Ig chimeras were able to both stain and activate an MCC-specific T cell hybridoma. Construction and expression of these two diverse heterodimers demonstrate the generality of this approach. Furthermore, the increased avidity of these soluble divalent proteins makes these chimeric molecules potentially useful in clinical settings for probing and modulating in vivo cellular responses.
Risk of recurrence and chemotherapy benefit for patients with node-negative, estrogen receptor-positive breast cancer: recurrence score alone and integrated with pathologic and clinical factors.

PURPOSE The 21-gene breast cancer assay recurrence score (RS) is widely used for assessing recurrence risk and predicting chemotherapy benefit in patients with estrogen receptor (ER) -positive breast cancer. Pathologic and clinical factors such as tumor size, grade, and patient age also provide independent prognostic utility. We developed a formal integration of these measures and evaluated its prognostic and predictive value. PATIENTS AND METHODS From the National Surgical Adjuvant Breast and Bowel (NSABP) B-14 and translational research cohort of the Arimidex, Tamoxifen Alone or in Combination (TransATAC) studies, we included patients who received hormonal monotherapy, had ER-positive tumors, and RS and traditional clinicopathologic factors assessed (647 and 1,088, respectively). Individual patient risk assessments from separate Cox models were combined using meta-analysis to form an RS-pathology-clinical (RSPC) assessment of distant recurrence risk. Risk assessments by RS and RSPC were compared in node-negative (N0) patients. RSPC was compared with RS for predicting chemotherapy benefit in NSABP B-20. RESULTS RSPC had significantly more prognostic value for distant recurrence than did RS (P < .001) and showed better separation of risk in the study population. RSPC classified fewer patients as intermediate risk (17.8% v 26.7%, P < .001) and more patients as lower risk (63.8% v 54.2%, P < .001) than did RS among 1,444 N0 ER-positive patients. In B-20, the interaction of RSPC with chemotherapy was not statistically significant (P = .10), in contrast to the previously reported significant interaction of RS with chemotherapy (P = .037). CONCLUSION RSPC refines the assessment of distant recurrence risk and reduces the number of patients classified as intermediate risk. Adding clinicopathologic measures did not seem to enhance the value of RS alone nor the individual biology RS identifies in predicting chemotherapy benefit.
The immunogenic part of infliximab is the F(ab′)2, but measuring antibodies to the intact infliximab molecule is more clinically useful

Objectives To localise the immunogenic part of infliximab and evaluate the clinical usefulness of measuring antibodies against infliximab fragments. Design Observational study. Settings A specialised inflammatory bowel disease (IBD) centre in a tertiary hospital. Interventions Serum was collected from patients with IBD and controls. Antibodies against whole infliximab (ATI) and against the digested Fc, F(ab′)2 and F(ab′) fragments were measured by a specifically developed ELISA and by western blotting. A separate ELISA was used to determine infliximab levels in serum. Results 109 serum samples from 62 infliximab-treated patients were tested along with 64 control samples. Anti-F(ab′)2 antibodies were found in 28/42 (67%) samples with positive ATI, all from infliximab-exposed patients. Anti-F(ab′)2 antibodies were also present in 26 of the remaining 67 (39%) samples from exposed patients despite absent ATI. No specific anti-Fc antibodies were detected. Low trough infliximab level and high ATI level was found in 10/12 patients (83%) with complete loss of response to infliximab, but in only 5/14 patients (36%, p=0.02) who regained response to intensified infliximab regimen and in 2/24 patients (8%, p<0.001) in maintained remission while on 5 mg/kg/8 week infliximab treatment. Although Anti-F(ab′)2 antibodies showed similar test characteristics to ATI in patients losing response to infliximab, they were also detected in 61% of patients in maintained remission, thereby limiting their clinical usefulness. No cross reactivity to adalimumab was noted. Conclusions F(ab′)2 is the immunogenic fragment of infliximab. However, ATI level in serum—combined with measurement of trough infliximab level—is better correlated with the clinical response to infliximab or with its loss.
MicroRNA-98 and let-7 Confer Cholangiocyte Expression of Cytokine-Inducible Src Homology 2-Containing Protein in Response to Microbial Challenge12

Posttranscriptional gene regulation by microRNAs (miRNAs) has been implicated in the fine-tuning of TLR-mediated inflammatory response. The cytokine-inducible Src homology 2-containing protein (CIS), one member of the suppressors of cytokine signaling family of proteins, is an important negative regulator for inflammatory cytokine signaling. Using in vitro models using normal human biliary epithelial cells (cholangiocytes), we demonstrated that LPS stimulation or infection with the parasitic protozoan Cryptosporidium parvum induced expression of CIS protein without a change in CIS mRNA levels by activating the TLR signaling pathway. Of those miRNAs expressed in cholangiocytes, we found that targeting of the 3′-untranslated region of CIS by microRNA-98 (miR-98) or let-7 resulted in translational repression, but not CIS mRNA degradation. LPS stimulation or C. parvum infection decreased cholangiocyte expression of miR-98 and let-7. Down-regulation of miR-98 and let-7 relieved miRNA-mediated translational suppression of CIS and contributed to LPS- and C. parvum-stimulated CIS protein expression. Moreover, gain-of-function (by overexpression of CIS) and loss-of-function (by siRNA interference) studies revealed that CIS could enhance IκBα degradation and regulate NF-κB activation in cholangiocytes in response to LPS stimulation or C. parvum infection. Our data suggest that miR-98 and let-7 confer cholangiocyte expression of CIS in response to microbial challenge, a process that may be relevant to the regulation of TLR-mediated epithelial innate immune response.
Risk factors for opioid overdose and awareness of overdose risk among veterans prescribed chronic opioids for addiction or pain

ABSTRACT Rising overdose fatalities among U.S. veterans suggest veterans taking prescription opioids may be at risk for overdose. However, it is unclear whether veterans prescribed chronic opioids are aware of this risk. The objective of this study was to identify risk factors and determine awareness of risk for opioid overdose in veterans treated with opioids for chronic pain, using veterans treated with methadone or buprenorphine for opioid use disorder as a high-risk comparator group. In the current study, 90 veterans on chronic opioid medication, for either opioid use disorder or pain management, completed a questionnaire assessing risk factors, knowledge, and self-estimate of risk for overdose. Nearly all veterans in both groups had multiple overdose risk factors, although individuals in the pain management group had on average a significantly lower total number of risk factors than did individuals in the opioid use disorder group (5.9 versus 8.5, p < .0001). On average, participants treated for pain management scored slightly but significantly lower on knowledge of opioid overdose risk factors (12.1 versus 13.5, p < .01). About 70% of participants, regardless of group, believed their overdose risk was below that of the average American adult. There was no significant relationship between self-estimate of overdose risk and either number or knowledge of opioid overdose risk factors. Our results suggest that veterans in both groups underestimated their risk for opioid overdose. Expansion of overdose education to include individuals on chronic opioids for pain management and a shift in educational approaches to overdose prevention may be indicated.
A closer look at transcription intelligibility for speakers with dysarthria: evaluation of scoring paradigms and linguistic errors made by listeners.

PURPOSE This study addressed the effects of 3 different paradigms for scoring orthographic transcriptions of dysarthric speech on intelligibility scores. The study also examined whether there were differences in transcription accuracy among words from different linguistic classes. METHOD Speech samples were collected from 12 speakers with dysarthria of varying severity. Twelve different listeners made orthographic transcriptions of each speaker, for a total of 144 listeners. Transcriptions were scored using 3 different paradigms: total word phonemic match, informational word phonemic match, and informational word semantic match. Transcriptions were also coded into 3 linguistic categories: content words, modifiers, and functors. The number of words that each listener transcribed correctly within each category was tallied. RESULTS There were significant differences among the 3 scoring paradigms. However, the magnitude of differences was relatively small. In addition, listeners transcribed functor words more accurately than content words or modifiers. They also transcribed free morphemes more accurately than bound morphemes. CONCLUSIONS The specific scoring paradigm that clinicians employ for measuring speech intelligibility appears to be relatively inconsequential as long as consistent procedures are used. Analyses of the kinds of words that listeners transcribe correctly suggest that interventions focusing on listener processing strategies should be considered for enhancing intelligibility of speakers with chronic dysarthria.
p21-Activated Kinases Cla4 and Ste20 Regulate Vacuole Inheritance in Saccharomyces cerevisiae

ABSTRACT Each time Saccharomyces cerevisiae cells divide they ensure that both the mother and daughter cell inherit a vacuole by actively transporting a portion of the vacuole into the bud. As the mother cell begins budding, a tubular and vesicular segregation structure forms that is transported into the bud by the myosin V motor Myo2, which is bound to the vacuole-specific myosin receptor, Vac17 (41, 59, 70, 79). Upon arriving in the bud the segregation structure is resolved to found the daughter vacuole. The mechanism that regulates segregation structure resolution in a spatially dependent manner is unknown. In addition to resolving the segregation structure, Vac17 is degraded specifically in the bud to provide directionality to vacuole inheritance. It has been proposed that bud-specific degradation of Vac17 is promoted by proteins localized to or activated solely in the bud (77). The p21-activated kinases (PAKs) Cla4 and Ste20 are localized to and activated in the bud. Here we report that Cla4 is localized to the segregation structure just prior to segregation structure resolution, and cells lacking PAK function fail to resolve the segregation structure. Overexpression of either Cla4 or Ste20 inhibited vacuole inheritance and this inhibition was suppressed by the expression of nondegradable VAC17. Finally, PAK activity was required for Vac17 degradation in late M phase and CLA4 overexpression promoted Vac17 degradation. We propose that Cla4 and Ste20 are bud-specific proteins that play roles in both segregation structure resolution and the degradation of Vac17.