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This article examines an under-explored topic of labor precarity of Chinese feminist and LGBT NGO activism from the perspective of social reproduction. Contextualizing the intimate connection between the Chinese party-state outsourcing social service delivery to global civil society and the burgeoning of feminist and LGBT NGOs since the 1990s, it argues that the party-state relies on the social reproductive functions of these NGO while containing their political influence; at the same time, the transnational non-profit funding complex utilized these NGOs for political intervention in China. Arguing against a binary framework of civil society versus state and resistance versus oppression, this article centers the lived experiences of feminist and LGBT activist workers and highlights the contradiction and interplay of agency and conformity of these workers in the state- and market- orchestrated processes of moralization, illegalization, and professionalization, whereby they reshape, revise, or reinforce norms associated with gender, sexuality, and neoliberal standards of productivity and efficiency. Building on Marxist feminist theorization of labor, this article valorizes NGO labor as socially valued work and calls for attention to the issue of labor precarity of NGO activist workers under the backdrop of increasing state violence and market cooptation in many parts of the world, especially in the global South. [ABSTRACT FROM AUTHOR]

• Adjuvant human papillomavirus vaccination among patients with history of dysplasia are low. • Physician counseling rates regarding vaccination among this population have not been studied. • Vaccination rates and physician counseling regarding vaccination in this cohort remain low. We describe provider documented counseling patterns and perception regarding HPV vaccination among patients with a history of cervical dysplasia. All patients ages 21–45 who underwent colposcopy at a single academic medical center from 2018 to 2020 were sent a self-administered survey through the electronic medical record patient portal to assess their attitudes regarding human papillomavirus (HPV) vaccination. Demographic information, HPV vaccination history, and documented obstetrics and gynecology provider counseling at the time of colposcopy were examined. Of 1465 patients, 434 (29.6 %) reported or had documented receipt of at least one dose of the human papillomavirus vaccine. The remainder reported they were not vaccinated or had no documentation of vaccination. Proportion of vaccinated patients was higher among White compared to Black and Asian patients (P = 0.02). On multivariate analysis, private insurance (aOR 2.2, 95 % CI 1.4–3.7) was associated with vaccinated status while Asian race (aOR 0.4, 95 % CI 0.2–0.7) and hypertension (aOR 0.2, 95 % CI 0.08–0.7) were less likely to be associated with vaccination status. Among patients with unvaccinated or unknown vaccination status, 112 (10.8 %) received documented counseling regarding catch-up human papillomavirus vaccination at a gynecologic visit. Patients seen by a sub-specialist obstetrics and gynecologic provider were more likely to have documented provider counseling regarding vaccination compared to those seen by a generalist obstetric/gynecologist provider (26 % vs 9.8 %, p < 0.001). Patients cited lack of physician discussion (53.7 %) and the belief that they were too old to receive the HPV vaccine (48.8 %) as the main reasons for remaining unvaccinated. HPV vaccination and the rate of obstetric and gynecologic provider counseling regarding HPV vaccination among patients undergoing colposcopy remains low. When surveyed, many patients with a history of colposcopy cited provider recommendation as a factor in their decision to undergo adjuvant HPV vaccination, demonstrating the importance of provider counseling in this group. [ABSTRACT FROM AUTHOR]

Refined risk stratification for gastroenteropancreatic neuroendocrine tumors (GEP‐NETs) has the potential to improve comparisons of study populations across clinical trials and facilitate drug development. Tumor growth rate (TGR) is a radiological metric with demonstrated prognostic value in well differentiated grade 1 and 2 (G1–2) GEP‐NETs, but little is known about TGR in G3 NETs. In this retrospective study of 48 patients with advanced G1–3 GEP‐NET, we calculated baseline TGR (TGR0) from radiological images of metastases acquired prior to first‐line therapy and evaluated its association with disease characteristics and outcomes. The median pretreatment Ki67 proliferation index for G1–3 tumors combined was 5% (range = 0.1%–52%) and median TGR0 was 4.8%/month (m) (range = 0%–45.9%/m). TGR0 correlated with pretreatment Ki67 across G1–3 pooled and within G3 GEP‐NET. Patients with higher TGR0 (>11.7%/m) tumors, which were primarily G3 pancreatic NETs, exhibited decreased time to first therapy (median, 2.2 vs. 5.3 months; p =.03) and shorter overall survival (median, 4.1 years vs. not reached; p =.003). Independent of therapies given, higher TGR0 GEP‐NETs experienced a greater incidence of Ki67 increase (100 vs. 50%; p =.02) and greater magnitude of Ki67 change (median, 14.0 vs. 0.1%; p =.04) upon serial biopsy. Importantly, TGR0, but not grade, predicted for future Ki67 increase in this series. Given the heterogeneity of well differentiated GEP‐NETs, future clinical trials may benefit from stratification for TGR0, particularly in G1–2 tumors, in which TGR0 does not correlate with Ki67. TGR0 has the potential to noninvasively identify patients with previously undiagnosed grade progression and those in whom more or less frequent monitoring may be appropriate. Additional research is needed to determine the prognostic and predictive value of TGR0 in larger and more homogeneously treated cohorts, and to ascertain if post‐treatment TGR has value in previously treated patients starting a new line of therapy. [ABSTRACT FROM AUTHOR]

Design failure modes, effects, and criticality analysis (d-FMECA) 2 2 The term FMEA and FMECA are used interchangeably throughout this paper. The user has the option in the interface to choose either FMEA or FMECA based on their desired application. is a bottom-up, semi-quantitative risk assessment approach that is used by reliability engineers across all industries (nuclear, chemical, environmental, pharmaceuticals, aerospace, etc.) for identifying the effects of postulated components failure modes such as solenoid-operated valves (SOV), motor-operated valves (MOV), controllers, pumps, sensors of various types, printed circuit boards (PCBs). This research aims to develop a novel AI-augmented tool that guides, in real-time, the risk-analyst to a host of potential failure modes and their effects for each component contained in a bigger system. Through a user-friendly graphical interface and a robust statistical modeling backend, the AI-driven tool streamlines the risk assessment process by prompting the risk analyst to input a system's name and subsequently generate an extensive array of failure modes and associated effects for each constituent component within the system. This AI-augmented tool allows the user to select either a simplified d-FMEA or a detailed d-FMECA for the system under investigation. This novel AI-driven tool offers significant effort and time savings in conducting d-FMECA, which is known to be a labor-intensive engineering task. In addition, this tool can be used for training risk and reliability professionals. • Developed a novel AI-augmented tool to replace conventional d-FMEA approach. • Designed a user-friendly graphical interface & robust statistical modeling backend. • This AI-driven tool offers significant effort & time savings in conducting d-FMECA. • Help train junior reliability engineers to effectively conduct d-FMEA. [ABSTRACT FROM AUTHOR]

We study popular attitudes in Germany, Spain, the Philippines, and the United States toward three controversial markets— prostitution, surrogacy, and global kidney exchange (GKE). Of those markets, only prostitution is banned in the United States and the Philippines, and only prostitution is allowed in Germany and Spain. Unlike prostitution, majorities support legalization of surrogacy and GKE in all four countries. So, there is not a simple relation between public support for markets, or bans, and their legal and regulatory status. Because both markets and bans on markets require social support to work well, this sheds light on the prospects for effective regulation of controversial markets. [ABSTRACT FROM AUTHOR]

The article presents a study related to the efficient blockade of locally reciprocated tumor-macrophage signaling using a tumor-associated macrophages (TAM)-avid nanotherapy. It mentions that the intravital microscopy simultaneously monitored in situ single-cell activities of multiple kinases downstream of receptor tyrosine kinases (RTKs), revealing MAPKi increased TAMs and enhanced bypass signaling in TAM-proximal tumor cells.

The article explores cooperative marriage between Lalas (lesbians) and Gay Men in Urban China. Particular focus is given to how this relates to the the term Tongzhi, which has been used to describe LGBTQ people in China. The film "The Wedding Banquet," directed by Ang Lee and released in 1993 is also noted. The role gender performance plays in marriage and family in China is also examined.

Adnexal mass and torsion are relatively uncommon, but potentially emergent complaints among pediatric and adolescent patients in the emergency department (ED) and surgical intervention is sometimes indicated. There is little national data evaluating surgical prevalence and outcomes within this population. This is a retrospective cross-sectional study utilizing the Nationwide Emergency Department Sample (NEDS) of hospital owned EDs throughout the United States from 2016 to 2018. Inclusion criteria included female sex, younger than 20 years old, and a diagnosis of adnexal mass or ovarian/tubal torsion by ICD-10 (International Classification of Diseases) codes. Other variables included age, ED disposition, type of hospital, region of the country, and teaching hospital status. Surgery status (binomial) was determined utilizing the ICD-10 PCS (Procedure Coding System) and included all ICD-10 CPS related to surgery on the adnexa. Descriptive and bivariate analyses were conducted to assess demographic findings and rates of admission and surgical intervention. Funded by the NASPAG Young Investigator Grant for 2021-2022. N=2,269 pediatric and adolescent patients presented to the emergency department from 2016-2018 with a diagnosis of either adnexal mass or ovarian/tubal torsion. 33.1% (n=751) of patients were admitted to the hospital and 15.1% (n=342) underwent adnexal surgery. Mean age of presentation was 15.3 years old. 63% (n=1,437) were 15 years or older and 35.7% (n=811) were 10 to 14 years old. Most of the expected payors were Medicaid (45.4%, n=1,028) and private insurance (45.5%, n=1,031). 38% of the patients presented to a hospital in the south and 25% in the northeast. 77% presented to a metropolitan, teaching hospitals, 16% metropolitan, non-teaching, and 6.3% non-metropolitan, non-teaching hospitals. There were no differences in patients who received surgery versus no surgery by insurance type, region, or urban-rural hospital distinction. There were higher odds of receiving surgery if at a teaching hospital compared to a non-teaching, metropolitan hospital (OR 1.83, 95% CI 1.2-2.7). Approximately one-third of patients with an adnexal mass or torsion diagnosis were admitted to the hospital and half of those patients ultimately received surgery. This is the first known study to date evaluating prevalence of surgical intervention within this population. Surgery was more likely at teaching hospitals; however, this study does not account for differences in acuity. Further analysis will focus on differentiation between adnexal mass and torsion, type of surgery (oophorectomy versus cystectomy), and mode of surgery (open versus laparoscopy). [ABSTRACT FROM AUTHOR]

Objectives: Human papillomavirus (HPV) vaccination reduces the risk of high-grade dysplasia and cervical cancer. We evaluated patterns in demographics and attitudes regarding HPV vaccination among women with prior colposcopy as a risk factor for cervical cancer. Methods: Women aged 21-45 years who underwent colposcopy at an academic medical center between October 1, 2018-October 31, 2020 were e-mailed a self-administered structured questionnaire including demographic variables and "yes/no" statements to assess the attitudes of those receiving versus those not receiving the HPV vaccine. Categorical demographic variables were analyzed using Chi-square or Fisher's exact test. Binary logistic regression was performed to determine associations between vaccination and demographic variables. Results: A total of 206 responses were received from the 1331 patients (15.8%); 60% of respondents (n =126) reported receiving the HPV vaccine. On univariate analysis, the White race, private insurance status, and higher education were positively associated with HPV vaccination. African American race and current or former tobacco use were negatively associated with vaccination (Table 1). After adjusting for covariates, patients with a college degree or higher education were 11-fold more likely to be vaccinated (OR: 11.3, 95% CI: 1.2-103.1). Current or former smokers were less likely to be vaccinated (OR: 0.3, 95% CI: 0.1-0.7). Common reasons cited for not receiving the vaccine included that it was not offered by the physician (53.7%) and that the patient believed she was too old (48.8%). Only 7.3% of respondents cited insurance as a reason for not being vaccinated. Among those who received the HPV vaccine, patients cited believing the vaccine could prevent HPV-related cancer (73.2%), believing the vaccine to be safe (66.1%), and provider recommendation (48.8%) as reasons for receiving the vaccine. Conclusions: Education level and smoking status are independent predictors of HPV vaccination in a high-risk group of women. Our results highlight the importance of physician recommendations for vaccination, as well as the importance of patient and physician education regarding indications and age range for HPV vaccination. Patients did not frequently cite insurance as a barrier to vaccination. [ABSTRACT FROM AUTHOR]

Background: To date, single-agent immune checkpoint inhibitor (CPI) therapy has proven to be ineffective against biomarker-unselected extrapulmonary poorly differentiated neuroendocrine carcinomas (EP-PDNECs). The efficacy of CPI in combination with chemotherapy remains under investigation. Methods: Patients with advanced, progressive EP-PDNECs were enrolled in a two-part study of pembrolizumab-based therapy. In Part A, patients received pembrolizumab alone. In Part B, patients received pembrolizumab plus chemotherapy. Primary endpoint: objective response rate (ORR). Secondary endpoints: safety, progression-free survival (PFS) and overall survival (OS). Tumours were profiled for programmed death-ligand 1 expression, microsatellite-high/mismatch repair deficient status, mutational burden (TMB), genomic correlates. Tumour growth rate was evaluated. Results: Part A (N = 14): ORR (pembrolizumab alone) 7% (95% CI, 0.2–33.9%), median PFS 1.8 months (95% CI, 1.7–21.4), median OS 7.8 months (95% CI, 3.1–not reached); 14% of patients (N = 2) had grade 3/4 treatment-related adverse events (TRAEs). Part B (N = 22): ORR (pembrolizumab plus chemotherapy) 5% (95% CI, 0–22.8%), median PFS 2.0 months (95% CI, 1.9–3.4), median OS 4.8 months (95% CI, 4.1–8.2); 45% of patients (N = 10) had grade 3/4 TRAEs. The two patients with objective response had high-TMB tumours. Discussion: Treatment with pembrolizumab alone and pembrolizumab plus chemotherapy was ineffective in advanced, progressive EP-PDNECs. Clinical trial registration: ClinicalTrials.gov NCT03136055. [ABSTRACT FROM AUTHOR]

When beginning a phototherapy regimen for a patient, consideration of compliance rates is important. Compliance to phototherapy can be affected by several factors, including the grade of discomfort and side effects from therapy, failure of previous therapies, accessibility and convenience to reach the phototherapy center, grade of improvement during phototherapy, patient relief due to light therapy, and rapport with staff. Understanding how these factors can affect patient adherence can allow for phototherapy regimens to be tailored in a manner that optimizes health outcomes and allows for proper patient selection. [ABSTRACT FROM AUTHOR]

Light therapy has been incorporated into the art of healing and cosmesis for thousands of years and currently has found utility in many areas of medicine. Various modalities of cosmetic phototherapy are detailed, as well as the indications and mechanism of action for each modality. These modalities can be used to treat many common cosmetic conditions, including acne vulgaris, solar lentigo, and melasma. Phototherapy is considered a safe and effective option in the treatment of many of these disorders. [ABSTRACT FROM AUTHOR]

An 18-year-old African American male with a history of congenital lymphedema of the right upper extremity presented for evaluation of multiple verrucous lesions on his right hand. Clusters of 2 to 4-mm dome-shaped vesicles were intermixed with scattered verrucous papules on the right forearm and the dorsal and palmar aspects of the hand. Histopathology of one the verrucous lesions showed well-circumscribed areas of dilated lymphatic vascular channels with lymph in the lumen. The patient was diagnosed with microcystic lymphatic malformation, verrucous type. This article reviews the literature regarding reports of this variant of microcystic lymphatic malformation in the pediatric population. [ABSTRACT FROM AUTHOR]

Administrative monopolies are a rampant problem in China. The Anti-Monopoly Law of the People's Republic of China (AML) attempts to deal with this problem by prohibiting government entities from abusing administrative power in anti-competitive ways. This article explores the effectiveness and enforcement of the administrative monopoly provisions by first looking at the treatment of administrative monopoly cases under the AML. The cases highlight not only the weaknesses of China's legal and judicial enforcement mechanisms, but also the important role of extra-legal mechanisms, such as the public pressure for rectification of violations. Second, China's situation is compared to that of Ukraine. The Ukrainian experience shows that the key elements to effective enforcement are providing for clear legislative penalties and having a strong and independent enforcement authority. Therefore, this article finds that, while the AML appears to have had some effect on reining in administrative monopolies, enforcement can be vastly improved by establishing an anti-monopoly enforcement agency that is independent, well resourced and empowered to take direct action against contraventions. Accordingly, the article concludes with some recommendations for short term and long term reform. [ABSTRACT FROM AUTHOR]

Abstract: Several recent studies in experimental economics have tried to measure beliefs of subjects engaged in strategic games with other subjects. Using data from one such study we conduct an experiment where our experienced subjects observe early rounds of strategy choices from that study and are given monetary incentives to report forecasts of choices in later rounds. We elicit beliefs using three different scoring rules: linear, logarithmic, and quadratic. We compare forecasts across the scoring rules and compare the forecasts of our trained observers to forecasts of the actual players in the original experiment. We find significant differences across scoring rules. The improper linear scoring rule produces forecasts closer to 0 and 1 than the proper rules, and these forecasts are poorly calibrated. The two proper scoring rules induce significantly different distributions of forecasts. We find that forecasts by observers under both proper scoring rules are significantly different from the forecasts of the actual players, in terms of accuracy, calibration, and the distribution of forecasts. We also find evidence for belief convergence among the observers. [Copyright &y& Elsevier]

Abstract: Background: Brain ischemia is the underlying cause of neuron death during stroke and brain trauma. Neural cells exposed to ischemia can undergo apoptosis. Adrenomedullin (AM) in combination with its enhancing binding protein, AMBP-1, has been shown to reduce tissue damage in inflammation. Methods: To evaluate a beneficial effect of AM/AMBP-1 administration in brain ischemia, we employed an in vitro model of neuronal hypoxia using differentiated human neuroblastoma SH-SY5Y cells. Results: After exposure to 1% O2 for 20 h, neural cells were injured with decreased ATP levels and increased LDH release. Pre-administration of AM/AMBP-1 significantly reduced hypoxia-induced cell injury. Moreover, AM/AMBP-1 treatment reduced the number of TUNEL-positive cells and activation of caspase-3, compared to cells exposed to hypoxia alone. AM/AMBP-1 prevented a reduction of cAMP levels and protein kinase A (PKA) activity in neural cells after hypoxia exposure. Correspondingly, an elevation of cAMP levels by forskolin protected neural cells from hypoxia-induced injury. Inhibition of PKA by KT5720 abolished the protective effect of AM/AMBP-1 on hypoxia-induced apoptosis. Conclusions: AM/AMBP-1 elevates cAMP levels, followed by activating PKA, to protect neural cells from the injury caused by hypoxia. General significance: AM/AMBP-1 may be used as therapeutic agents to prevent neuron damage from brain ischemia. [Copyright &y& Elsevier]

The article describes the rising impact of networked technologies in Asia. It summarizes the diverse and unsettled regulatory reactions evolving in Asia in response to fundamental changes brought about by networked technologies. It describes the varied impact of the Internet and mobile technologies from country to country.

Summary: Protein inhibitors of proteolytic enzymes regulate proteolysis and prevent the pathological effects of excess endogenous or exogenous proteases. Cysteine proteases are a large family of enzymes found throughout the plant and animal kingdoms. Disturbance of the equilibrium between cysteine proteases and natural inhibitors is a key event in the pathogenesis of cancer, rheumatoid arthritis, osteoporosis, and emphysema. A family (I42) of cysteine protease inhibitors (http://merops.sanger.ac.uk) was discovered in protozoan parasites and recently found widely distributed in prokaryotes and eukaryotes. We report the 2.2 Å crystal structure of the signature member of the I42 family, chagasin, in complex with a cysteine protease. Chagasin has a unique variant of the immunoglobulin fold with homology to human CD8α. Interactions of chagasin with a target protease are reminiscent of the cystatin family inhibitors. Protein inhibitors of cysteine proteases may have evolved more than once on nonhomologous scaffolds. [Copyright &y& Elsevier]

MicroRNAs (miRNAs) are a family of ≈22-nt noncoding RNAs that can posttranscriptionally regulate gene expression. Several miR-NAs are specifically expressed in hematopoietic cells. Here we show that one such miRNA, miR-150, is mainly expressed in the lymph nodes and spleen and is highly up-regulated during the development of mature T and B cells; expression of miR-150 is sharply up-regulated at the immature B cell stage. Overexpression of miR-150 in hematopoietic stem cells, followed by bone marrow transplantation, had little effect on the formation of either mature CD8- and CD4-positive T cells or granulocytes or macrophages, but the formation of mature B cells was greatly impaired. Furthermore, premature expression of miR-150 blocked the transition from the pro-B to the pre-B stage. Our results indicate that miR-150 most likely down-regulates mRNAs that are important for pre- and pro-B cell formation or function, and its ectopic expression in these cells blocks further development of B cells. [ABSTRACT FROM AUTHOR]

Falcipain-2 (FP2), the major cysteine protease of the human malaria parasite Plasmodium falciparum, is a hemoglobinase and promising drug target. Here we report the crystal structure of FP2 in complex with a protease inhibitor, cystatin. The FP2 structure reveals two previously undescribed cysteine protease structural motifs, designated FP2nose and FP2arm, in addition to details of the active site that will help focus inhibitor design. Unlike most cysteine proteases, FP2 does not require a prodomain but only the short FP2nose motif to correctly fold and gain catalytic activity. Our structure and mutagenesis data suggest a molecular basis for this unique mechanism by highlighting the functional role of two Tyr within FP2nose and a conserved Glu outside this motif. The FP2arm motif is required for hemoglobinase activity. The structure reveals topographic features and a negative charge cluster surrounding FP2arm that suggest it may serve as an exo-site for hemoglobin binding. Motifs similar to FP2nose and FP2arm are found only in related plasmodial proteases, suggesting that they confer malaria-specific functions. [ABSTRACT FROM AUTHOR]

Endospore formation by Bacillus subtilis involves three differentiating cell types, the predivisional cell, the mother cell, and the forespore. Here we report the program of gene expression in the forespore, which is governed by the RNA polymerase sigma factors σF and σG and the DNA-binding proteins RsfA and SpoVT. The σF factor turns on about 48 genes, including the gene for RsfA, which represses a gene in the σF regulon, and the gene for σG. The σG factor newly activates 81 genes, including the gene for SpoVT, which turns on (in nine cases) or stimulates (in 11 cases) the expression of 20 genes that had been turned on by σG and represses the expression of 27 others. The forespore line of gene expression consists of many genes that contribute to morphogenesis and to the resistance and germination properties of the spore but few that have metabolic functions. Comparative genomics reveals a core of genes in the σF and σG regulons that are widely conserved among endospore-forming species but are absent from closely related, but non-spore-forming Listeria spp. Two such partially conserved genes (ykoU and ykoV), which are members of the σG regulon, are shown to confer dry-heat resistance to dormant spores. The ykoV gene product, a homolog of the non-homologous end-joining protein Ku, is shown to associate with the nucleoid during germination. Extending earlier work on gene expression in the predivisional cell and the mother cell, we present an integrated overview of the entire program of sporulation gene expression. [Copyright &y& Elsevier]

Falcipain-2 (FP2) is a papain family cysteine protease and important hemoglobinase of erythrocytic Plasmodium falciparum parasites Inhibitors of FP2 block hemoglobin hydrolysis and parasite development suggesting that this enzyme is a promising target for antimalarial chemotherapy. FP2 and related plasmodial cysteine proteases have an unusual 14-aa motif near the C terminus of the catalytic domain. Recent solution of the structure of FP2 showed this motif to form a β-hairpin that is distant from the enzyme active site and protrudes out from the protein. To evaluate the function of this motif, we compared the activity of the wild-type enzyme with that of a mutant lacking 10 aa of the motif (Δ10FP2). Δ10FP2 had nearly identical activity to that of the wild-type enzyme against peptide substrates and the protein substrates casein and gelatin. However, Δ10FP2 demonstrated negligible activity against hemoglobin or globin. FP2 that was inhibited with trans-epoxysuccinyl- L-leucylamido-(4-guanidino)butane (FP2E-64) formed a complex with hemoglobin, but Δ10Fp2E-64 did not indicating that the motif mediates binding to hemoglobin independent of the active site. A peptide encoding the motif blocked hemoglobin hydrolysis, but not the hydrolysis of casein. Kinetics for the inhibition of Δ10FP2 were very similar to those for FP2 with peptidyl and protein inhibitors, but Δ10FP2 was poorly inhibited by the inhibitory prodomain of FP2. Our results indicate that FP2 utilizes an unusual motif for two specific functions, interaction with hemoglobin, its natural substrate, and interaction with the prodomain, its natural inhibitor. [ABSTRACT FROM AUTHOR]

Filamentous soil bacteria of the genus Streptomyces carry out complex developmental cycles that result in sporulation and production of numerous secondary metabolites with pharmaceutically important activities. To further characterize the molecular basis of these developmental events, we screened for mutants of Streptomyces coelicolor that exhibit aberrant morphological differentiation and/or secondary metabolite production. On the basis of this screening analysis and the subsequent complementation analysis of the mutants obtained we assigned developmental roles to a gene involved in methionine biosynthesis (metH) and two previously uncharacterized genes (SCO6938 and SCO2525) and we reidentified two previously described developmental genes (bldA and bldM). In contrast to most previously studied genes involved in development, the genes newly identified in the present study all appear to encode biosynthetic enzymes instead of regulatory proteins. The MetH methionine synthase appears to be required for conversion of aerial hyphae into chains of spores, SCO6938 is a probable acyl coenzyme A dehydrogenase that contributes to the proper timing of aerial mycelium formation and antibiotic production, and SCO2525 is a putative methyltransferase that influences various aspects of colony growth and development. [ABSTRACT FROM AUTHOR]

In visual search tasks, if a set of items is presented for 1 s before another set of new items (containing the target) is added, search can he restricted to the new set. The process that eliminates old items from search is visual marking. This study investigates the kind of memory that distinguishes the old items from the new items during search. Using an accuracy paradigm in which perfect marking results in 100% accuracy and lack of marking results in near chance performance, the authors show that search can be restricted to new items not by visual short-term memory (VSTM) of old locations but by a limited capacity and slow-decaying VSTM of new locations and a high capacity and last-decaying memory for asynchrony. [ABSTRACT FROM AUTHOR]

The serine protease factor Xa (FXa) is inhibited by ecotin with picomolar affinity. The structure of the tetrameric complex of ecotin variant M84R (M84R) with FXa has been determined to 2.8 Å. Substrate directed induced fit of the binding interactions at the S2 and S4 pockets modulates the discrimination of the protease. Specifically, the Tyr at position 99 of FXa changes its conformation with respect to incoming ligand, changing the size of the S2 and S4 pockets. The role of residue 192 in substrate and inhibitor recognition is also examined. Gln 192 from FXa forms a hydrogen bond with the P2 carbonyl group of ecotin. This confirms previous biochemical and structural analyses on thrombin and activated protein C, which suggested that residue 192 may play a more general role in mediating the interactions between coagulation proteases and their inhibitors. The structure of ecotin M84R-FXa (M84R-FXa) also reveals the structure of the Gla domain in the presence of Mg[sup 2+]. The first 11 residues of the domain assume a novel conformation and likely represent an intermediate folding state of the domain. [ABSTRACT FROM AUTHOR]

Investigates the conformational changes and interactions of the crystal structure of thrombin and ecotin. Results of point mutation (M84R) in ecotin; Determination of crystal structure of bovine thrombin; Interaction of thrombin and ecotin M84R in distinct surfaces.

To define the incidence, prognosis, and treatment patterns associated with multiple primary lower genital tract squamous cell carcinoma (LGTSCC). Surveillance, Epidemiology, and End Results (SEER) database patients diagnosed with synchronous cervical, vaginal, vulvar, and/or anal SCC from 2000-2016 were included. Incidence and mortality were evaluated using Kaplan-Meier curves. Multivariable Cox proportional hazards regression was used to identify treatment patterns, risk factors, and mortality associated with LGTSCC. Among 15,424 women with any LGTSCC, 138 patients had multiple primary LGTSCC (0.89%). Vulvar and vaginal SCC was the most common combination (49.3%), and cervical with anal SCC was the least common (1.4%). Only one patient had 3 or more primary LGTSCC (vulvar, cervical, and anal). Multiple primary LGTSCC was independently associated with higher mortality compared to single site LGTSCC (adjusted hazards ratio [aHR]=1.67; p<0.001). Multiple primary LGTSCC was significantly associated with older age (63 vs. 58 years, p<0.001) and have lower stage (adjusted odds ratio [aOR]=0.38; p<0.001) and grade of disease (aOR=0.32; p<0.001). Patients with multiple primary LGTSCC were more likely to receive radiation overall (aOR=1.74, p=0.005) and were more likely to receive adjuvant radiation after primary surgical resection compared to single site LGTSCC (aOR=1.88, p=0.007). Receipt of any treatment including radiation (aHR=0.85; p<0.001), chemotherapy (aHR=0.50; p<0.001), and surgery (aHR=0.70; p<0.001) was independently associated with decreased mortality hazard. Multiple primary LGTSCC is rare but is associated with increased mortality, and higher rates of adjuvant radiation compared to single site LGTSCC despite lower stage and grade at diagnosis. More research is needed to define optimal therapy for patients with multiple primary LGTSCC. [ABSTRACT FROM AUTHOR]

To identify correlations between disease recurrence and adherence to NCCN posttreatment surveillance guidelines in patients who develop recurrent uterine cancer. Retrospective analysis identified patients (n = 60) with recurrent uterine cancer and at least one surveillance visit with a gynecologic oncologist between 2011 and 2020. Adherence to NCCN guidelines and details of recurrence were recorded. Recurrent uterine cancer was identified in 60 patients with an average time to recurrence (TTR) of 25 months. Of those, 39 (65%) were adherent to NCCN surveillance guidelines and 36 (60%) were symptomatic at the time of recurrence diagnosis. Asymptomatic recurrence was diagnosed by imaging in 11 (46%), physical exam in 7 (29%), and blood work in 6 (25%) patients. Patients who were adherent to NCCN guidelines were diagnosed with recurrence on average 11 months earlier (p = 0.0336). Adherence was an independent predictor of TTR for all patients regardless of symptoms. There was no significant effect of age, race, primary language, or stage of disease on adherence. Adherence to NCCN posttreatment surveillance guidelines for uterine cancer is independently associated with an earlier diagnosis of recurrence. • Many patients are not adherent to NCCN surveillance guidelines at time of recurrence detection. • Physical exam is an important for detecting uterine cancer recurrence. • Non-NCCN directed imaging detected almost half of asymptomatic recurrences. • Asymptomatic recurrence is detected earlier in patients who adhere to NCCN posttreatment surveillance guidelines. [ABSTRACT FROM AUTHOR]

Joubert syndrome is a group of rare disorders that stem from defects in a sensory organelle, the primary cilia. Affected patients often present with disorders involving multiple organ systems, including the brain, eyes, and kidneys. Common symptoms include breathing abnormalities, mental developmental delays, loss of voluntary muscle coordination, and abnormal eye movements, with a diagnostic "molar tooth" sign observed by magnetic resonance imaging (MRI) of the midbrain. We reviewed the ocular phenotypes that can be found in patients with Joubert syndrome. Ocular motor apraxia is the most frequent (80% of patients), followed by strabismus (74%) and nystagmus (72%). A minority of patients also present with ptosis (43%), chorioretinal coloboma (30%), and optic nerve atrophy (22%). Although mutations in 34 genes have been found to be associated with Joubert syndrome, retinal degeneration has been reported in only 38% of patients. Mutations in AHI1 and CEP290, genes critical to primary cilia function, have been linked to retinal degeneration. In conclusion, Joubert syndrome is a rare pleiotropic group of disorders with variable ocular presentations. [ABSTRACT FROM AUTHOR]

Engaging people with lived experience of mental health system encounters in the design and actualization of continuing professional development initiatives for mental health professionals can have transformative systemic impacts. Yet, despite evidence that involving people with lived experience benefits mental health professional education, far less focus has been placed on how to engage people with lived experience in continuing professional development initiatives. Tensions persist regarding the role of lived experience perspectives in continuing professional development, as well as how to establish people with lived experience as partners, educators and leaders in a thoughtful way. We propose that meaningful and equitable partnerships with people with lived experience can be realized by engaging in critical reflexivity and by systematically challenging assumptions. This paper explores three topics: (1) the current state of engagement with people with lived experience in continuing professional development initiatives; (2) barriers to meaningful engagement and (3) recommendations for using critical reflexivity to support the involvement and leadership of people with lived experience in continuing professional development for mental health professionals. Patient or Public Involvement: This viewpoint manuscript was co‐designed and co‐written by people with diverse lived and learned experiences. Each author's professional roles involve meaningfully and equitably partnering with and centring the perspectives of those with lived experience of mental health system encounters. In addition, approximately half of the authorship team identifies as having lived experience of accessing the psychiatric system and/or supporting family members who are navigating challenges related to mental health. These lived and learned experiences informed the conception and writing of this article. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented on the use of melanoma simulation models in dermatology exams, responding to the 2012 article "Recognition of melanoma: A dermatologic clinical competency in medical student education," by J. M. Goulart, S. Dusza, A. Pillsbury, R. P. Soriano, A. C. Halpern, and A. A. Marghoob, and the 2013 article "Assessing students' ability to detect melanomas using standardized patients and moulage," by C. Hernandez, R. Mermelstein, J. K. Robinson, and R. Yudkowsky.

Highlights • PBMCs from caregivers have increased proinflammatory gene expression levels when stimulated in vitro compared to controls. • These genes include NF-κB and many of its cytokine and chemokine targets. • PBMCs from caregivers showed increased Th17 differentiation and increased expression of COX-2 signaling pathway. • Inflammatory gene expression is associated with shorter telomere length prospectively. Abstract The chronic psychological stress of caregiving leads to higher risks for many diseases. One of the mechanisms through which caregiving is associated with disease risk is chronic inflammation. Chronic inflammation may accelerate cellular aging via telomere dysfunction and cell senescence, although this has not been examined in human cells from healthy people. We examined peripheral blood mononuclear cells (PBMCs) from 20 healthy mothers of children with autism (caregivers) and 19 mothers of neurotypical children (controls) in an in vitro culture system where PBMCs were stimulated with phytohaemagglutinin (PHA). We measured RNA expression levels of a panel of immune function genes before and after PHA stimulation, as well as telomere length from PBMCs collected from the participants at baseline and 15 months later. Caregivers and controls had similar gene expression profiles in unstimulated PBMCs, but after PHA stimulation, caregivers had increased RNA levels of the master inflammatory regulator NF-κB and its proinflammatory cytokine targets IL-1β, IL-6 and its receptor IL-6R as well as inflammatory chemokines IL-8, CXCL1 and CXCL2. Gene expression analysis suggested caregivers have increased Treg and Th17 T cell differentiation. Additionally, key signaling molecules involved in the upregulation of COX-2, a critical enzyme in the synthesis of the inflammatory mediator prostaglandin, were elevated. When both groups were examined together, higher expression levels of proinflammatory genes were associated with shorter telomere length in PBMCs from blood drawn 15 months later, independent of baseline telomere length. Taken together, these results suggest that chronic stress is associated with an exaggerated inflammatory response in PBMCs, which in turn is associated with shorter telomere length measured from PBMCs collected 15 months later. To our knowledge, this is the first human study that shows increased proinflammatory expression predicts future telomere shortening. [ABSTRACT FROM AUTHOR]

Actinic keratoses (AKs) are atypical, precancerous proliferations of keratinocytes that develop because of chronic exposure to ultraviolet (UV) radiation. Treatment of AK can be lesion-directed or field-directed. Field cancerization theory postulates that the skin surrounding AK is also at increased risk for possible malignant transformation since it has been exposed to the same chronic UV light. Field-directed therapies thus have the potential to address subclinical damage, reduce AK recurrence rates, and potentially reduce the risk of squamous cell carcinoma (SCC) development. Published clinical studies have found lesion clearance rates ranging from 81 to 91% for photodynamic therapy (PDT) with either aminolevulinic acid (ALA) or methylaminolevulinate (MAL). Clinical studies have also been published on various topical treatments. Complete clinical clearance (CCC) was significantly higher in patients treated with a combination of 5-fluorouracil and salicylic acid (5-FU-SA) than in the vehicle group across multiple studies, and CCC ranged between 46 and 48% following treatment with imiquimod. Additionally, treatment with diclofenac sodium (DFS) found reduction in lesion sizes to range from 67 to 75%. Reported results have been similar for another non-steroidal anti-inflammatory drug (NSAID), piroxicam, which has more cyclooxygenase (COX)-1 activity than DFS. Active treatments with ingenol mebutate were also significantly more effective than vehicle at clearing AK lesions. All treatments resulted in mild, localized skin reactions. PDT using conventional light sources was associated with increased severity of pain and/or discomfort, while PDT using daylight as the light source was associated with less pain and occasionally no pain at all. Though no widely accepted algorithm for the treatment of AKs exists, field-directed therapy can be particularly useful for treating photo-exposed areas containing multiple AKs. Additional research with more direct comparisons between these field-directed therapies will help clinicians determine the best therapeutic approach. Here, we provide a balanced and comprehensive narrative review of the literature, considering both light-based and topical therapies with a focus on their field-therapy aspects, and propose a therapeutic algorithm for selecting an appropriate treatment in the clinical setting. [ABSTRACT FROM AUTHOR]

Background: Cytomegalovirus (CMV) infection leads to effector memory CD8+ T cell expansion and is associated with immune dysfunction in older adults. However, the molecular alterations of CMV-specific CD8+ T cells in CMV infected healthy young and middle-aged adults has not been fully characterized. Results: We compared CD8+ T cells specific for a CMV epitope (pp65495-503, NLV) and an influenza A virus (IAV) epitope (M158-66, GIL) from the same young and middle-aged healthy adults with serum positive for anti-CMV IgG. Compared to the IAV-specific CD8+ T cells, CMV-specific CD8+ T cells contained more differentiated effector memory (TEM and TEMRA) cells. Isolated CMV-specific central memory (TCM) but not naïve (TN) cells had a significant reduced activation-induced expansion in vitro compared to their IAV-specific counterparts. Furthermore, we found that CD70 expression was reduced in CMV-specific CD28+CD8+ TCM and that CD70+ TCM had better expansion in vitro than did CD70- TCM. Mechanistically, we showed that CD70 directly enhanced MAPK phosphorylation and CMV-specific CD8+ TCM cells had a reduced MAPK signaling upon activation. Lastly, we showed that age did not exacerbate reduced CD70 expression in CMV- specific CD8+ TCM cells. Conclusion: Our findings showed that CMV infection causes mild expansion of CMV-NLV-specific CD8+ T cells, reduced CD70 expression and signaling, and proliferation of CMV-NLV-specific CD8+ TCM cells in young and middle-aged healthy adults and revealed an age-independent and CMV infection-specific impact on CD8+ memory T cells. [ABSTRACT FROM AUTHOR]

Backgrounds: A loop ileostomy may reduce the severity of acute anastomotic complications after low rectal resection, but some patients have persistent rectal anastomotic problems. No consensus exists for the management of patients with a chronic low rectal anastomosis complication and a loop ileostomy. There is need for a standard description of these anastomotic complications and to determine whether it is safe to reverse the ileostomy. This study proposes a classification of chronic rectal anastomotic complications and to report the correlation with successful restoration of rectal continuity. Methods: This was a retrospective project from a prospectively maintained database at a single colorectal unit in a large tertiary hospital in Metropolitan Melbourne. Patients with rectal anastomotic complications following rectal cancer resections between March 2012 and October 2019 were included. A classification of chronic rectal anastomotic complication was developed by reviewing the interval assessments of the rectal anastomosis. The classification categories were correlated with outcomes after stoma closure. Results: Of the 149 patients, 20 patients had an anastomotic complication identified during work up prior to loop ileostomy reversal. Eleven patients had an anastomotic stenosis and nine had an anastomotic defect. Eighteen patients were eligible for stomal closure. The majority (11/12) of patients with a Type 1 stenosis or defect had no rectal complications after stoma closure. Conclusion: The classification system helps to describe chronic rectal anastomotic abnormalities and guide management. Although these patients may be a challenge, many can undergo successful ileostomy reversal. [ABSTRACT FROM AUTHOR]

Opioid overdose suppresses brainstem respiratory circuits, causes apnoea and may result in death. Epidural electrical stimulation (EES) at the cervical spinal cord facilitated motor activity in rodents and humans, and we hypothesized that EES of the cervical spinal cord could antagonize opioid‐induced respiratory depression in humans. Eighteen patients requiring surgical access to the dorsal surface of the spinal cord between C2 and C7 received EES or sham stimulation for up to 90 s at 5 or 30 Hz during complete (OFF‐State) or partial suppression (ON‐State) of respiration induced by remifentanil. During the ON‐State, 30 Hz EES at C4 and 5 Hz EES at C3/4 increased tidal volume and decreased the end‐tidal carbon dioxide level compared to pre‐stimulation control levels. EES of 5 Hz at C5 and C7 increased respiratory frequency compared to pre‐stimulation control levels. In the OFF‐State, 30 Hz cervical EES at C3/4 terminated apnoea and induced rhythmic breathing. In cadaveric tissue obtained from a brain bank, more neurons expressed both the neurokinin 1 receptor (NK1R) and somatostatin (SST) in the cervical spinal levels responsive to EES (C3/4, C6 and C7) compared to a region non‐responsive to EES (C2). Thus, the capacity of cervical EES to oppose opioid depression of respiration may be mediated by NK1R+/SST+ neurons in the dorsal cervical spinal cord. This study provides proof of principle that cervical EES may provide a novel therapeutic approach to augment respiratory activity when the neural function of the central respiratory circuits is compromised by opioids or other pathological conditions. Key points: Epidural electrical stimulation (EES) using an implanted spinal cord stimulator (SCS) is an FDA‐approved method to manage chronic pain.We tested the hypothesis that cervical EES facilitates respiration during administration of opioids in 18 human subjects who were treated with low‐dose remifentanil that suppressed respiration (ON‐State) or high‐dose remifentanil that completely inhibited breathing (OFF‐State) during the course of cervical surgery.Dorsal cervical EES of the spinal cord augmented the respiratory tidal volume or increased the respiratory frequency, and the response to EES varied as a function of the stimulation frequency (5 or 30 Hz) and the cervical level stimulated (C2–C7).Short, continuous cervical EES restored a cyclic breathing pattern (eupnoea) in the OFF‐State, suggesting that cervical EES reversed the opioid‐induced respiratory depression.These findings add to our understanding of respiratory pattern modulation and suggest a novel mechanism to oppose the respiratory depression caused by opioids. [ABSTRACT FROM AUTHOR]

The article discusses a study on the impact of diabetes mellitus on the collection of hematopoietic stem cells and hematologic recovery post-transplantation in a group of patients. The study examined patient data from Washington University School of Medicine in Saint Louis, Missouri. Hierarchical logistic multivariate regression was performed to develop a model of optimal stem cell collection. The results showed the association of DM with stem cell mobilization.

Abstract: Targeted therapy for the treatment of cancers using nanoparticles (NPs) decorated with transferrin (Tf) has been relatively successful, as several such nanocarriers are currently undergoing clinical trials. However, since native Tf has a low probability of delivering its payload due to its short residence time in the cell, or low cellular association, there is room to significantly improve the potency of current systems. We pioneered the redesign of this targeting ligand by altering the ligand–metal interaction, as suggested by our mathematical model, and here we present the first study to investigate the enhanced therapeutic efficacy of NPs conjugated to our engineered oxalate Tf. Our mathematical model was first used to predict that NPs conjugated to oxalate Tf will exhibit a higher degree of cellular association compared to native Tf-conjugated NPs. Our in vitro trafficking experiments validated the model prediction, and subsequent in vitro and in vivo efficacy studies demonstrated that this increase in cellular association further translates into an enhanced ability to deliver chemotherapeutics. Our findings signify the importance of the cellular trafficking properties of targeting ligands, as they may significantly influence therapeutic potency when such ligands are conjugated to NPs. Given the early success of a number of native Tf-conjugated NPs in clinical trials, there is potential for using Tf-variant based therapeutics in systemic drug delivery applications for cancer treatment. [Copyright &y& Elsevier]

Hindsight bias is the tendency to retrospectively think of outcomes as being more foreseeable than they actually were. It is a robust judgment bias and is difficult to correct (or “debias”). In the experiments reported here, we used a visual paradigm in which performers decided whether blurred photos contained humans. Evaluators, who saw the photos unblurred and thus knew whether a human was present, estimated the proportion of participants who guessed whether a human was present. The evaluators exhibited visual hindsight bias in a way that matched earlier data from judgments of historical events surprisingly closely. Using eye tracking, we showed that a higher correlation between the gaze patterns of performers and evaluators (shared attention) is associated with lower hindsight bias. This association was validated by a causal method for debiasing: Showing the gaze patterns of the performers to the evaluators as they viewed the stimuli reduced the extent of hindsight bias. [ABSTRACT FROM PUBLISHER]

Objective To test the hypothesis that economic recessions lead to reduced global development assistance for health (DAH). Methods Data obtained from the Creditor Reporting System of the Organisation for Economic Co-operation and Development (OECD) for 15 OECD countries were used to model the percentage change (relative difference) in commitments and disbursements for DAH as a function of three measures of economic recession: recessionary year (as a dummy variable with 0 for no recession and 1 for recession), percentage change in per capita gross domestic product and percentage point change in unemployment rate for recessionary cycles from 1975 through 2007. We looked for an association both during the concurrent recessionary year and one and two years later. Findings No statistically significant association was found in the short or long run between measures of economic recession and the amount of official DAH committed or disbursed. Conclusion Any important decrease in overall DAH following the current economic recession would have little historical precedent and claims of inevitability would be unjustifiable. [ABSTRACT FROM AUTHOR]

Porous brittle solids evidence complex mechanical behavior, where localized failure patterns originate from mechanical processes on the microstructural level. In order to investigate the failure mechanics of porous brittle solids, we outline a general stochastic and numerical microstructure-based approach. To this end, we generate random porous microstructures by level-cutting Gaussian random fields, and conduct numerical simulations using the material point method. This allows investigating both small and large deformation characteristics of irregular porous media where a segmentation into grains and bonds is ambiguous. We demonstrate the versatility of our approach by examining elasticity and failure as a function of a wide range of porosities, from 20% to 80%. Observing that onset of failure can be well described through the second order work, we show that the stress at failure follows a power law similar to that of the elastic modulus. Moreover, we propose that the failure envelope can be approximated by a simple quadratic fitting curve, and that plastic deformation appears to be governed by an associative plastic flow rule. Finally, large deformation simulations reveal a transition in the mode of localization of the deformation, from compaction bands for highly porous samples to shear bands for denser ones. [ABSTRACT FROM AUTHOR]

This study described sleep in a heterogeneous sample of breast cancer patients using the Pittsburgh Sleep Quality Index (PSQI) and examined the relation between sleep disturbance and health-related quality of life as measured by the Rand 36-Item Health Survey. Chemotherapy and radiation therapy were explored as predictors of sleep disturbance in breast cancer patients, and the sleep characteristics of breast cancer patients were compared to the sleep characteristics of a sample of medical patients with general medical conditions. Results showed that 61% of breast cancer patients had significant sleep problems. Sleep was characterized by reduced total sleep time with sleep frequently being disturbed by pain, nocturia, feeling too hot, and coughing or snoring loudly. Despite the frequency of significant sleep disturbance, pharmacological and cognitive–behavioral treatments of sleep problems were observed to be inadequate. Limited evidence was found for the role of chemotherapy and radiation therapy in the sleep disturbance of breast cancer patients, and the general pattern of sleep disturbance in breast cancer patients was not significantly different than that observed in medical patients with general medical conditions. Breast cancer patients having significant sleep problems had greater deficits in many areas of health-related quality of life. The implications of the findings and study limitations are discussed. [Copyright &y& Elsevier]

The article focuses on the study of acoustic variation in speech, particularly in the context of conversations involving opinion convergence and divergence. It mentions how factors like the duration of interaction and speaker's responses to differing opinions influence speech patterns, using topics such as "Plant versus Animal Regenerative Farming," "ProLife versus Pro-Choice," and "Vegan versus Animal Foods" as examples to investigate these dynamics.