Miracle-dz/UniFAR-FTUs huggingface dataset:
Combined immunotherapy with nivolumab and ipilimumab with and without local therapy in patients with melanoma brain metastasis: a DeCOG* study in 380 patients

Background Nivolumab combined with ipilimumab have shown activity in melanoma brain metastasis (MBM). However, in most of the clinical trials investigating immunotherapy in this subgroup, patients with symptomatic MBM and/or prior local brain radiotherapy were excluded. We studied the efficacy of nivolumab plus ipilimumab alone or in combination with local therapies regardless of treatment line in patients with asymptomatic and symptomatic MBM. Methods Patients with MBM treated with nivolumab plus ipilimumab in 23 German Skin Cancer Centers between April 2015 and October 2018 were investigated. Overall survival (OS) was evaluated by Kaplan-Meier estimator and univariate and multivariate Cox proportional hazard analyses were performed to determine prognostic factors associated with OS. Results Three hundred and eighty patients were included in this study and 31% had symptomatic MBM (60/193 with data available) at the time of start nivolumab plus ipilimumab. The median follow-up was 18 months and the 2 years and 3 years OS rates were 41% and 30%, respectively. We identified the following independently significant prognostic factors for OS: elevated serum lactate dehydrogenase and protein S100B levels, number of MBM and Eastern Cooperative Oncology Group performance status. In these patients treated with checkpoint inhibition first-line or later, in the subgroup of patients with BRAFV600-mutated melanoma we found no differences in terms of OS when receiving first-line either BRAF and MEK inhibitors or nivolumab plus ipilimumab (p=0.085). In BRAF wild-type patients treated with nivolumab plus ipilimumab in first-line or later there was also no difference in OS (p=0.996). Local therapy with stereotactic radiosurgery or surgery led to an improvement in OS compared with not receiving local therapy (p=0.009), regardless of the timepoint of the local therapy. Receiving combined immunotherapy for MBM in first-line or at a later time point made no difference in terms of OS in this study population (p=0.119). Conclusion Immunotherapy with nivolumab plus ipilimumab, particularly in combination with stereotactic radiosurgery or surgery improves OS in asymptomatic and symptomatic MBM.
An Emerging Landscape for Canonical and Actionable Molecular Alterations in Primary and Metastatic Prostate Cancer

Patients with prostate cancer with tumors harboring defects in DNA-repair genes (DRD) generally do not respond well to AR-directed therapy. Furthermore, canonical pathways evolve during disease progression and may affect treatment with existing therapies. Due to the limited treatment options after failure of hormonal and taxane therapy, and the tumor heterogeneity induced by DRD, we sought to characterize the alterations in primary and metastatic prostate cancer. Tumors from 1,027 patients with advanced prostate cancer that underwent comprehensive genomic profiling for routine clinical care were reviewed to assess DRD mutation rates (27-gene panel) and co-occurring mutations in select canonical prostate cancer pathways. DRD alterations were identified in 20 genes and in 17% of patients (BRCA2 and ATM most common) occurring with slightly higher frequency in specimens from metastatic biopsy sites and men older than 50 years of age. Microsatellite instability-high (MSI-H) and tumor mutational burden-high occurred with 3% frequency in the overall cohort but were not enriched in metastatic disease. Biomarkers previously associated with antitumor immunity are found at high frequencies in MSI-H patients, including JAK1 (68%) and PTEN (32%). Lastly, mutations in TP53, AR, PTEN, APC, CTNNB1, and PIK3CA were all significantly enriched in metastatic samples. We identified clinically significant subgroups of patients demonstrating (1) defects in DNA-repair pathways, (2) intrinsic prostate cancer signaling pathways that may prevent antitumor immunity, and (3) distinct genomic differences between localized and metastatic prostate cancer. These results lend support that genomic profiling for advanced prostate cancer may identify actionable targets not routinely used in the current metastatic paradigm.
Characterization of tumor mutation burden, PD-L1 and DNA repair genes to assess relationship to immune checkpoint inhibitors response in metastatic renal cell carcinoma

Background Immune checkpoint inhibitors (ICIs) have expanded treatment options for metastatic renal cell carcinoma (mRCC); however, there are limited predictive biomarkers for response to ICIs in this indication, with programmed death-ligand 1 (PD-L1) status demonstrating little predictive utility in mRCC. While predictive of ICI response in other tumor types, the utility of tumor mutation burden (TMB) in mRCC is unclear. Here, we assess TMB, loss of antigen presentation genes and PD-L1 status correlated with outcomes to ICI treatment in mRCC. Methods Tumor samples from 34 patients with mRCC treated with ICI therapy at Duke Cancer Institute were retrospectively evaluated using Personal Genome Diagnostics elio tissue complete (RUO version), a tumor genomic profiling assay for somatic variants, TMB, microsatellite status and genomic status of antigen presentation genes. Tumor samples were also analyzed with the Dako 28-8 PD-L1 immunohistochemistry assay. Deidentified clinical information was extracted from the medical record, and tumor response was evaluated based on the Response Evaluation Criteria In Solid Tumors (RECIST) V.1. 1 criteria. Results Patients were stratified by overall response following ICI therapy and designated as progressive disease (PD; n=18) or disease control groups (DC; n=16). TMB scores ranged from 0.36 to 12.24 mutations/Mb (mean 2.83 mutations/Mb) with no significant difference between the PD and DC groups (3.01 vs 2.63 mutations/Mb, respectively; p=0.7682). Interestingly, 33% of PD patients displayed loss of heterozygosity of major histocompatibility complex class I genes (LOH-MHC) vs 6% of DC patients. Nine of 34 samples were PD-L1-positive (4 in the PD group; 5 in the DC group), suggesting no correlation between PD-L1 expression and response to ICI therapy. Notably, the DC group displayed an enrichment of mutations in DNA repair genes (p=0.04), with 68.8% exhibiting at least one mutated homologous recombination repair (HRR)-related gene compared with only 38.9% of the PD group (p=0.03). Conclusions Overall, neither TMB nor PD-L1 correlated with ICI response and TMB was not significantly associated with PD-L1 expression. The higher incidence of LOH-MHC in PD group suggests that loss of antigen presentation may restrict response to ICIs. Separately, enrichment of HRR gene mutations in the DC group suggests potential utility in predicting ICI response and a potential therapeutic target, warranting future studies.
Endovascular coiling versus surgical clipping for the treatment of unruptured cerebral aneurysms

Abstract Background: Endovascular coiling and surgical clipping are routinely used to treat unruptured cerebral aneurysms (UCAs). However, the evidence to support the efficacy of these approaches is limited. We aimed to analyze the efficacy of endovascular coiling compared with surgical clipping in patients with UCAs. Method: A systematic search of 4 databases was conducted to identify comparative articles involving endovascular coiling and surgical clipping in patients with UCAs. We conducted a meta-analysis using the random-effects model when I2> 50%. Otherwise, a meta-analysis using the fixed-effects model was performed. Results: Our results showed that endovascular coiling was associated with a shorter length of stay (WMD: −4.14, 95% CI: (−5.75, −2.531), P < . 001) and a lower incidence of short-term complications compared with surgical clipping (OR: 0.518; 95% CI (0.433, 0.621); P < . 001), which seems to be a result of ischemia complications (OR: 0.423; 95% CI (0.317, 0.564); P < . 001). However, surgical clipping showed a higher rate of complete occlusion after surgery, in both short-term (OR: 0.179, 95% CI (0.064, 0.499), P = . 001) and 1-year follow-ups (OR: 0.307, 95% CI (0.146, 0.646), P = . 002), and a lower rate of short-term retreatment (OR: 0.307, 95% CI (0.146, 0.646), P = . 002). Meanwhile, there was no significant difference in postoperative death, bleeding, and modified Rankin Scale (mRS) > 2 between the 2 groups. Conclusions: The latest evidence illustrates that surgical clipping resulted in lower retreatment rates and was associated with a higher incidence of complete occlusion, while endovascular coiling was associated with shorter LOS and a lower rate of complications, especially ischemia.
Knowledge of Mothers with Regard to Immunisation of Children in Vhembe District, Limpopo Province

Abstract The Extended Programme on Immunisation aims at delivering the primary immunisation series to at least 90 percent of infants. It is considered essential for improving infant and child survival. Inspite of the importance of immunisation on child survival, the coverage at the Tshino-Mutsha local area dropped from 85 percent to 75 percent during 2011-2012. The purpose of this study was to determine the knowledge of mothers’ regarding immunisation of children below 6 years of age. A quantitative research approach, cross-sectional survey was used and simple random sampling was undertaken to sample 200 mothers at seven clinics, including the mobile clinic. Self-administered questionnaires were used to collect data. The Statistical Package for Social Sciences was used to analyze data. Findings indicated that illiterate mothers and those younger than 35 years with less than 3 children were more knowledgeable with regard to the importance of Immunisation. The government health facilities, especially at the primary level need to be more users-friendly by making it accessible to all and also by creating opportunities of information sharing on immunisation for mothers. Awareness campaigns and capacity building would empower mothers on immunisation.
A Critical Role of Formyl Peptide Receptors in Host Defense against Escherichia coli

Key Points Fprs (FPRs in humans) interact with E. coli–derived chemotactic ligands. Fprs mediate neutrophil recruitment in response to E. coli products. Fpr-deficient mice show increased mortality to E. coli infection. Formyl peptide receptors (FPRs, mouse Fprs) belong to the G protein–coupled receptor superfamily and mediate phagocyte migration in response to bacteria- and host-derived chemoattractants; however, knowledge about their in vivo roles in bacterial pathogenesis is limited. In this study, we investigated the role of Fpr1 and Fpr2 in host defense against Escherichia coli infection. In vitro, we found that supernatants from E. coli cultures induced chemotaxis of wild-type (WT) mouse bone marrow–derived neutrophils and that the activity was significantly reduced in cells genetically deficient in either Fpr1 or Fpr2 and was almost absent in cells lacking both receptors. Consistent with this, E. coli supernatants induced chemotaxis and MAPK phosphorylation in HEK293 cells expressing either recombinant Fpr1 or Fpr2 but not untransfected parental cells. WT bone marrow –derived neutrophils could actively phagocytose and kill E. coli, whereas both activities were diminished in cells lacking Fpr1 or Fpr2; again, an additive effect was observed in cells lacking both receptors. In vivo, Fpr1 and Fpr2 deficiency resulted in reduced recruitment of neutrophils in the liver and peritoneal cavity of mice infected with inactivated E. coli. Moreover, Fpr1−/− and Fpr2−/− mice had significantly increased mortality compared with WT mice after i.p. challenge with a virulent E. coli clinical isolate. These results indicate a critical role of Fprs in host defense against E. coli infection.
Implications of HLA diversity among regions for bone marrow donor searches in Japan

Japan is an island country, and the Japanese people have had minimal genetic exchange with other ethnolinguistic groups. Consequently, the population is highly uniform and has limited HLA diversity relative to people from other countries. However, Japan has three ethnolinguistic groups, and HLA distributions differ depending on geographic region. To collect an HLA‐rich variety of bone marrow bank donor registrants, it is essential to know the precise distribution of HLA in Japan. We analyzed HLA alleles and haplotypes based on HLA information of 177 041 bone marrow donor registrants. Registrants were grouped depending on the prefecture and region (a group of prefectures) as commonly used in Japan. The prefectures did not show the same distributions, but the tendency was similar for each region. We found that Okinawa Prefecture and the mainland can be clearly divided as haplotypes: [A*24:02‐C*01:02‐B*54:01‐DRB1*04:05] and [A*24:02‐C*01:02‐B*59:01‐DRB1*04:05] were typically found in Okinawa (P = .02, P < .001). Moreover, these types were found almost exclusively in Japan and Korea. Donor registration centers of the Japan Marrow Donor Program are currently located in all prefectures. It is essential to deploy registration centers to collect registrants with a large variety of HLA types covering all of Japan.
The value, impact and role of nurses in rheumatology outpatient care: Critical review of the literature.

BACKGROUND As rheumatology nurses make substantial contributions to intensive management programmes following 'treat to target' principles of people with rheumatoid arthritis (RA), there is a need to understand the impacts of their involvement. A structured literature review was undertaken of qualitative studies, clinical trials and observational studies to assess the impacts of rheumatology nurses on clinical outcomes and the experiences of patients with RA and to examine the skills and training of the nurses involved. METHOD A structured literature review was conducted to examine the value, impact and professional role of nurses in RA management. RESULTS The literature search identified 657 publications, and 20 of them were included comprising: seven qualitative studies (242 patients), nine trials (a total of 2,440 patients) and four observational studies (1,234 patients). In clinical trials, nurses achieved similar patient clinical outcomes to doctors, and nurses also enhanced patients' satisfaction of received care and self-efficacy. In the qualitative studies reviewed, the nurses increased patients' knowledge and promoted their self-management. The observational studies studied examined found that nursing care led to improved patients' global functioning. The nurses in the various studies had a wide range of titles, experiences and training. DISCUSSION Our structured literature review provides strong evidence that rheumatology nurses are effective in delivering care for RA patients. However, their titles, experience and training were highly variable. CONCLUSION There is a convincing case to maintain and extend the role of nurses in managing RA, but further work is needed on standardisation of their titles and training.
Recent biological invasion shapes species recognition and aggressive behavior in a native species: a behavioral experiment using robots in the field.

Invasive species are a worldwide threat to biodiversity. Yet, our understanding of biological invasions remains incomplete, partly due to the difficulty of tracking and studying behavioral interactions in recently created species interactions. We tested whether the interactions between the recently introduced invasive lizard Anolis cristatellus and the native Anolis oculatus in Dominica have led to changes in species recognition and aggressive behavior of the native species. The use of realistic robots allowed us to test the behavioral response of 131 A. oculatus males towards relevant and controlled conspecific vs. heterospecific stimuli, directly in the field and in two contexts (allopatry vs. sympatry). Our results show that species recognition evolved prior to sympatry in A. oculatus. Moreover, interspecific competition resulted in an increase in the time spent displaying and a divergence in the aggressive behavior of the native species toward conspecifics vs. heterospecifics. Inherent species recognition and higher aggressive behavior may limit species coexistence as they are expected to favor A. oculatus during territorial interactions with A. cristatellus. While more studies are needed to understand the causes of these behavioral shifts and their consequences on long-term species coexistence, the present study highlights the role of behavior as a first response to interspecific interactions.
Could the glycosylation analysis of seminal plasma clusterin become a novel male infertility biomarker?

Male infertility is becoming a rapidly growing problem around the world, mainly in the highly developed countries. Seminal proteome composition seems to be one of the crucial factors of the proper course of fertilization ‐ clusterin (CLU) is among the most important ones. CLU, as one of the crucial seminal plasma glycoproteins, plays a very important role in sperm capacitation and immune tolerance in the female reproductive tract. CLU is also known as a sensitive marker of oxidative stress. It has six n‐glycosylation sites and also exhibits chaperone activity. An analysis of changes in the profile and degree of CLU glycosylation may shed some new light on the molecular mechanisms of the fertilization process and may be used as an additional diagnostic marker of male fertility. This study constitutes a review of the recently available literature concerning human seminal CLU, including changes in its glycosylation, analyzed in the context of human reproduction.
United Arab Emirates Child Health Survey.

Detailed results from a survey on child survival and reproductive health undertaken in the United Arab Emirates in 1987-1988 as part of the Gulf Child Health Survey are presented. The survey included a nationally representative probability sample of 6083 households. The report has chapters on survey design and implementation characteristics of households and respondents infant and child mortality disability diarrheal morbidity immunization breast-feeding and weaning practices maternity care marriage patterns and fertility. (ANNOTATION)
Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019

Summary Background The novel coronavirus SARS-CoV-2 is a newly emerging virus. The antibody response in infected patient remains largely unknown, and the clinical values of antibody testing have not been fully demonstrated. Methods A total of 173 patients with confirmed SARS-CoV-2 infection were enrolled. Their serial plasma samples (n = 535) collected during the hospitalization period were tested for total antibodies (Ab), IgM and IgG against SARS-CoV-2 using immunoassays. The dynamics of antibodies with the progress and severity of disease was analyzed. Findings Among 173 patients, the seroconversion rate for Ab, IgM and IgG was 93.1% (161/173), 82.7% (143/173) and 64.7% (112/173), respectively. Twelve patients who had not seroconverted were those only blood samples at the early stage of illness were collected. The seroconversion sequentially appeared for Ab, IgM and then IgG, with a median time of 11, 12 and 14 days, respectively. The presence of antibodies was < 40% among patients in the first 7 days of illness, and then rapidly increased to 100.0%, 94.3% and 79.8% for Ab, IgM and IgG respectively since day 15 after onset. In contrast, the positive rate of RNA decreased from 66.7% (58/87) in samples collected before day 7 to 45.5% (25/55) during days 15 to 39. Combining RNA and antibody detections significantly improved the sensitivity of pathogenic diagnosis for COVID-19 patients (p < 0.001), even in early phase of 1-week since onset (p = 0.007). Moreover, a higher titer of Ab was independently associated with a worse clinical classification (p = 0.006). Interpretation The antibody detection offers vital clinical information during the course of SARS-CoV-2 infection. The findings provide strong empirical support for the routine application of serological testing in the diagnosis and management of COVID-19 patients.
Evolution of hyperossification expands skull diversity in frogs

Significance The vertebrate head is an integrated system essential for sensory functions, capturing prey, and defense mechanisms. Head anatomy has long attracted the attention of biologists, yet identifying the factors responsible for the evolution of deviant morphological forms has remained a long-standing challenge. Frogs are one of the most diverse vertebrate orders but have not been thoroughly studied with respect to cranial morphological variation. We use extensive sampling of all major lineages to quantify skull diversity, reconstruct the evolution of increased mineralization (hyperossification), and test for relationships between ecology, skull shape, and hyperossification. We find that several extreme skull shapes have repeatedly evolved in frogs, hyperossification has arisen independently many times, and deviant skulls often cooccur with hyperossification and specialized functions. Frogs (Anura) are one of the most diverse vertebrate orders, comprising more than 7,000 species with a worldwide distribution and extensive ecological diversity. In contrast to other tetrapods, frogs have a highly derived body plan and simplified skull. In many lineages of anurans, increased mineralization has led to hyperossified skulls, but the function of this trait and its relationship with other aspects of head morphology are largely unexplored. Using three-dimensional morphological data from 158 species representing all frog families, we assessed wide-scale patterns of shape variation across all major lineages, reconstructed the evolutionary history of cranial hyperossification across the anuran phylogeny, and tested for relationships between ecology, skull shape, and hyperossification. Although many frogs share a conserved skull shape, several extreme forms have repeatedly evolved that commonly are associated with hyperossification, which has evolved independently more than 25 times. Variation in cranial shape is not explained by phylogenetic relatedness but is correlated with shifts in body size and ecology. The species with highly divergent, hyperossified skulls often have a specialized diet or a unique predator defense mechanism. Thus, the evolution of hyperossification has repeatedly facilitated the expansion of the head into multiple new shapes and functions.
Detection of serum immunoglobulin M and immunoglobulin G antibodies in 2019 novel coronavirus infected patients from different stages

Department of Laboratory Medicine, Fifth Hospital of Shijiazhuang, Hebei Medical University, Shijiazhuang, Hebei 050021, China; Department of Laboratory Medicine, Hospital of Xiongxian, Xiong’an New Area, Hebei 071800, China; Department of Tuberculosis, Fifth Hospital of Shijiazhuang, Hebei Medical University, Shijiazhuang, Hebei 050021, China; Intensive Care Unit, Fifth Hospital of Shijiazhuang, Hebei Medical University, Shijiazhuang, Hebei 050021, China.