To Fix or to Learn? How Production Bias Affects Developers’ Information Foraging during Debugging

Developers performing maintenance activities must balance their efforts to learn the code vs. their efforts to actually change it. This balancing act is consistent with the “production bias” that, according to Carroll’s minimalist learning theory, generally affects software users during everyday tasks. This suggests that developers’ focus on efficiency should have marked effects on how they forage for the information they think they need to fix bugs. To investigate how developers balance fixing versus learning during debugging, we conducted the first empirical investigation of the interplay between production bias and information foraging. Our theory-based study involved 11 participants: half tasked with fixing a bug, and half tasked with learning enough to help someone else fix it. Despite the subtlety of difference between their tasks, participants foraged remarkably differently—making foraging decisions from different types of “patches,” with different types of information, and succeeding with different foraging tactics

Open Source barriers to entry, revisited : a tools perspective

Software (OSS) communities and that women disproportionately experience such barriers. However, this research has focused mainly on social/cultural factors, ignoring the environment itself — the tools and infrastructure. To shed some light onto how tools and infrastructure might somehow factor into OSS barriers to entry, we conducted a field study with five teams of software professionals, who worked through five use-cases to analyze the tools and infrastructure used in their OSS projects. These software professionals found tool/infrastructure barriers in 7% to 71% of the use-case steps they analyzed, most of which are tied to newcomer barriers that have been established in the literature. Further, over 80% of the barrier types they found include attributes that are biased against women

Clinical, neuroradiological, and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder

PURPOSE: Biallelic variants in TARS2, encoding the mitochondrial threonyl-tRNA-synthetase, have been reported in a small group of individuals displaying a neurodevelopmental phenotype, but with limited neuroradiological data and insufficient evidence for causality of the variants. METHODS: Exome or genome sequencing was carried out in 15 families. Clinical and neuroradiological evaluation was performed for all affected individuals, including review of 10 previously reported individuals. The pathogenicity of TARS2 variants was evaluated using in vitro assays, and a zebrafish model. RESULTS: We report 18 new individuals harboring biallelic TARS2 variants. Phenotypically, these individuals show developmental delay/intellectual disability, regression, cerebellar and cerebral atrophy, basal ganglia signal alterations, hypotonia, cerebellar signs and increased blood lactate. In vitro studies showed that variants within the TARS2301-381 region had decreased binding to Rag GTPases, likely impairing mTORC1 activity. The zebrafish model recapitulated key features of the human phenotype and unraveled dysregulation of downstream targets of mTORC1 signaling. Functional testing of the variants confirmed the pathogenicity in a zebrafish model. CONCLUSION: We define the clinico-radiological spectrum of TARS2-related mitochondrial disease, unveil the likely involvement of the mTORC1 signaling pathway as a distinct molecular mechanism, and establish a TARS2 zebrafish model as an important tool to study variant pathogenicity

Intravital imaging technology guides FAK-mediated priming in pancreatic cancer precision medicine according to Merlin status

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic, chemoresistant malignancy and is characterized by a dense, desmoplastic stroma that modulates PDAC progression. Here, we visualized transient manipulation of focal adhesion kinase (FAK), which integrates bidirectional cell-environment signaling, using intravital fluorescence lifetime imaging microscopy of the FAK-based Förster resonance energy transfer biosensor in mouse and patient-derived PDAC models. Parallel real-time quantification of the FUCCI cell cycle reporter guided us to improve PDAC response to standard-of-care chemotherapy at primary and secondary sites. Critically, micropatterned pillar plates and stiffness-tunable matrices were used to pinpoint the contribution of environmental cues to chemosensitization, while fluid flow–induced shear stress assessment, patient-derived matrices, and personalized in vivo models allowed us to deconstruct how FAK inhibition can reduce PDAC spread. Last, stratification of PDAC patient samples via Merlin status revealed a patient subset with poor prognosis that are likely to respond to FAK priming before chemotherapy

Intravital imaging technology guides FAK-mediated priming in pancreatic cancer precision medicine according to Merlin status

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic, chemoresistant malignancy and is characterized by a dense, desmoplastic stroma that modulates PDAC progression. Here, we visualized transient manipulation of focal adhesion kinase (FAK), which integrates bidirectional cell-environment signaling, using intravital fluorescence lifetime imaging microscopy of the FAK-based Forster resonance energy transfer biosensor in mouse and patient-derived PDAC models. Parallel real-time quantification of the FUCCI cell cycle reporter guided us to improve PDAC response to standard-of-care chemotherapy at primary and secondary sites. Critically, micro-patterned pillar plates and stiffness-tunable matrices were used to pinpoint the contribution of environmental cues to chemosensitization, while fluid flow-induced shear stress assessment, patient-derived matrices, and personalized in vivo models allowed us to deconstruct how FAK inhibition can reduce PDAC spread. Last, stratification of PDAC patient samples via Merlin status revealed a patient subset with poor prognosis that are likely to respond to FAK priming before chemotherapy

Nucleotides Inhibition of HIV-1 Replication by Chemically Synthesized, Nuclease-Resistant, Nontoxic (2' 3 5')-Oligoadenylate Agonists

International audienc

Trauma‐informed patient and public‐engaged research: Development and evaluation of an online training programme

Abstract Introduction As patients, members of the public, and professional stakeholders engage in co‐producing health‐related research, an important issue to consider is trauma. Trauma is very common and associated with a wide range of physical and behavioural health conditions. Thus, it may benefit research partnerships to consider its impact on their stakeholders as well as its relevance to the health condition under study. The aims of this article are to describe the development and evaluation of a training programme that applied principles of trauma‐informed care (TIC) to patient‐ and public‐engaged research. Methods A research partnership focused on addressing trauma in primary care patients (‘myPATH’) explicitly incorporated TIC into its formation, governance document and collaborative processes, and developed and evaluated a free 3‐credit continuing education online training. The training was presented by 11 partners (5 professionals, 6 patients) and included academic content and lived experiences. Results Training participants (N = 46) positively rated achievement of learning objectives and speakers' performance (ranging from 4.39 to 4.74 on a 5‐point scale). The most salient themes from open‐ended comments were that training was informative (n = 12) and that lived experiences shared by patient partners were impactful (n = 10). Suggestions were primarily technical or logistical. Conclusion This preliminary evaluation indicates that it is possible to incorporate TIC principles into a research partnership's collaborative processes and training about these topics is well‐received. Learning about trauma and TIC may benefit research partnerships that involve patients and public stakeholders studying a wide range of health conditions, potentially improving how stakeholders engage in co‐producing research as well as producing research that addresses how trauma relates to their health condition under study. Patient or Public Contribution The myPATH Partnership includes 22 individuals with professional and lived experiences related to trauma (https://www.usf.edu/cbcs/mhlp/centers/mypath/); nine partners were engaged due to personal experiences with trauma; other partners are community‐based providers and researchers. All partners contributed ideas that led to trauma‐informed research strategies and training. Eleven partners (5 professionals, 6 patients) presented the training, and 12 partners (8 professionals, 4 patients) contributed to this article and chose to be named as authors

Determining the incidence of Pneumocystis pneumonia in patients with autoimmune blistering diseases not receiving routine prophylaxis

IMPORTANCE: Pneumocystis pneumonia (PCP) is a potentially lethal opportunistic infection that primary prophylaxis can help prevent. The risk of prophylactic therapy must be weighed against the incidence of PCP in the patient population. Prophylaxis most frequently involves trimethoprim-sulfamethoxazole, with second-line therapies, including atovaquone, dapsone, and pentamide. The indication for prophylaxis in immunocompromised patients without HIV is less well defined. Previously, an incidence of at least 3.5% has been proposed as a cutoff to justify prophylaxis. OBJECTIVE: To assess the incidence of PCP in patients with autoimmune blistering diseases receiving no routine prophylaxis. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective analysis of patient medical records to determine the incidence of PCP infections. The multicenter study was performed at tertiary care centers that provide care for patients with autoimmune blistering disease in Germany, Italy, Singapore, Israel, and the Netherlands. Patients had a confirmed diagnosis of pemphigus vulgaris/foliaceus, bullous pemphigoid, epidermolysis bullosa acquisita, mucous membrane pemphigoid/cicatricial pemphigoid, or anti-p200 pemphigoid. MAIN OUTCOMES AND MEASURES: To determine the incidence of PCP defined as patients with the International Classification of Diseases, Ninth Revision (ICD-9), code 136.3, for PCP, or free text documentation of PCP occurring based on characteristic radiographic findings with elevated lactate dehydrogenase, or hospitalization for pneumonia with bronchioalveolar lavage demonstrating Pneumocystis jiroveci on confirmatory stains. RESULTS: A total of 801 patients with autoimmune blistering diseases were included in this study; their mean (SD) age was 66.5 (17.6) years, and a total of 465 (58%) were female. Only 1 patient developed PCP, resulting in an incidence rate of 0.1%. This incidence significantly fell below the recommended threshold of 3.5% (0.1% vs 3.5%, \ucf\u8712= 27.0; P < .001). This incidence was significantly lower than the previously reported incidence of PCP in all immunosuppressed dermatologic patients (0.1% vs 1.3%; \ucf\u8712= 8.2; P = .004). CONCLUSIONS AND RELEVANCE: Routine Pneumocystis prophylaxis for patients with autoimmune blistering diseases does not seem to be warranted. Patients with autoimmune blistering disease seem to have a lower risk of PCP than the general population of immunosuppressed dermatology patients. Risks of routine prophylaxis include hyperkalemia, hypoglycemia, photosensitivity, thrombocytopenia, and more rare adverse reactions

Placental epigenetic clocks: estimating gestational age using placental DNA methylation levels

The human pan-tissue epigenetic clock is widely used for estimating age across the entire lifespan, but it does not lend itself well to estimating gestational age (GA) based on placental DNAm methylation (DNAm) data. We replicate previous findings demonstrating a strong correlation between GA and genome-wide DNAm changes. Using substantially more DNAm arrays (n=1,102 in the training set) than a previous study, we present three new placental epigenetic clocks: 1) a robust placental clock (RPC) which is unaffected by common pregnancy complications (e.g., gestational diabetes, preeclampsia), and 2) a control placental clock (CPC) constructed using placental samples from pregnancies without known placental pathology, and 3) a refined RPC for uncomplicated term pregnancies. These placental clocks are highly accurate estimators of GA based on placental tissue; e.g., predicted GA based on RPC is highly correlated with actual GA (r>0.95 in test data, median error less than one week). We show that epigenetic clocks derived from cord blood or other tissues do not accurately estimate GA in placental samples. While fundamentally different from Horvath’s pan-tissue epigenetic clock, placental clocks closely track fetal age during development and may have interesting applications.publishedVersio

Pemphigus. S2 Guideline for diagnosis and treatment--guided by the European Dermatology Forum (EDF) in cooperation with the European Academy of Dermatology and Venereology (EADV)

BACKGROUND Pemphigus encompasses a group of life-threatening autoimmune bullous diseases characterized by blisters and erosions of the mucous membranes and skin. Before the era of immunosuppressive treatment, the prognosis of pemphigus was almost fatal. Due to its rarity, only few prospective controlled therapeutic trials are available. OBJECTIVES For this reason, a group of European dermatologists with a long-standing interest and expertise in basic and clinical pemphigus research has sought to define diagnostic and therapeutic guidelines for the management of patients with pemphigus. RESULTS This group identified the statements of major agreement or disagreement regarding the diagnostic and therapeutic management of pemphigus. The revised final version of the pemphigus guideline was finally passed on to the European Dermatology Forum (EDF) for a final consensus with the European Academy of Dermatology and Venereology (EADV) and the European Union of Medical Specialists (UEMS)