Structural basis for mechanical force regulation of the adhesin FimH via finger trap-like beta sheet twisting.

The Escherichia coli fimbrial adhesive protein, FimH, mediates shear-dependent binding to mannosylated surfaces via force-enhanced allosteric catch bonds, but the underlying structural mechanism was previously unknown. Here we present the crystal structure of FimH incorporated into the multiprotein fimbrial tip, where the anchoring (pilin) domain of FimH interacts with the mannose-binding (lectin) domain and causes a twist in the beta sandwich fold of the latter. This loosens the mannose-binding pocket on the opposite end of the lectin domain, resulting in an inactive low-affinity state of the adhesin. The autoinhibition effect of the pilin domain is removed by application of tensile force across the bond, which separates the domains and causes the lectin domain to untwist and clamp tightly around the ligand like a finger-trap toy. Thus, beta sandwich domains, which are common in multidomain proteins exposed to tensile force in vivo, can undergo drastic allosteric changes and be subjected to mechanical regulation.

Treatment patterns and costs among US patients with diffuse large B-cell lymphoma not treated with 2L stem cell transplantation.

Aim: To assess treatment patterns, healthcare resource utilization (HCRU), and costs for patients with diffuse large B-cell lymphoma (DLBCL) who did not receive stem cell transplantation in second-line. Patients & methods: An administrative MarketScan® database study to assess DLBCL claims from 01/01/2009-30/09/2020. Results: Most patients (n = 750) received rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone in first-line (86.8%) and rituximab (39.5%) or bendamustine ± rituximab ± other (16.3%) in second-line. Over half were hospitalized (mean duration: 16.5 (standard deviation [SD]: 25.8) days per patient per year). Mean medical/pharmacy costs were US$141,532 per patient per year (SD: $189,579), driven by DLBCL-related claims. Conclusion: Healthcare resource utilization and costs for DLBCL-related claims were due to hospitalizations and outpatient visits. Novel therapies to reduce clinical and economic burdens are needed.

Novel Compound Heterozygous ZAP70 R37G A507T Mutations in Infant with Severe Immunodeficiency.

Zeta-chain associated protein kinase 70 kDa (ZAP70) combined immunodeficiency (CID) is an autosomal recessive severe immunodeficiency that is characterized by abnormal T-cell receptor signaling. Children with the disorder typically present during the first year of life with diarrhea, failure to thrive, and recurrent bacterial, viral, or opportunistic infections. To date, the only potential cure is hematopoietic stem cell transplant (HSCT). The majority of described mutations causing disease occur in the homozygous state, though heterozygotes are reported without a clear understanding as to how the individual mutations interact to cause disease. This case describes an infant with novel ZAP-70 deficiency mutations involving the SH2 and kinase domains cured with allogeneic HSCT utilizing a reduced-intensity conditioning regimen and graft manipulation. We then were able to further elucidate the molecular signaling alterations imparted by these mutations that lead to altered immune function. In order to examine the effect of these novel compound ZAP70 heterozygous mutations on T cells, Jurkat CD4+ T cells were transfected with either wild type, or with individual ZAP70 R37G and A507T mutant constructs. Downstream TCR signaling events and protein localization results link these novel mutations to the expected immunological outcome as seen in the patient's primary cells. This study further characterizes mutations in the ZAP70 gene as combined immunodeficiency and the clinical phenotype.

Antibody-Conjugated Nanodiamonds as Dual-Functional Immunosensors for In Vitro Diagnostics.

Nanodiamonds (NDs) are carbon nanoparticles with a large refractive index, a high density, and exceptional chemical stability. When excited by green light, they can emit bright red fluorescence from implanted nitrogen-vacancy (NV) centers. Taking advantage of these properties, we have developed antibody-conjugated NDs as in vitro diagnostic sensors for two complementary assays: particle-enhanced turbidimetric immunoassay (PETIA) and spin-enhanced lateral flow immunoassay (SELFIA). To achieve this goal, monocrystalline diamond powders (∼100 nm in diameter) with or without NV implantation were first treated in molten KNO3 to reduce their size and shape inhomogeneity, followed by surface carboxylation in strong oxidative acids and non-covalent conjugation with antibodies in water. PETIA and SELFIA were carried out separately with a microplate reader and a magnetically modulated fluorescence analyzer. Using C-reactive protein (CRP) as the target antigen, we found that anti-CRP-conjugated NDs exhibited high colloidal stability over 1 month at 4 °C in buffer solution. The limits of detection for 3 µL of CRP sample solution were 0.06 µg/mL and 1 ng/mL with variation coefficients of less than 10 and 15% for PETIA and SELFIA, respectively. These two methods together provide a detection range of 1 ng/mL-10 µg/mL, potentially useful for clinical applications. This work represents the first practical use of rounded monocrystalline NDs as in vitro diagnostic reagents.

Disrupting Sc-uORFs of a transcription factor bZIP1 using CRISPR/Cas9 enhances sugar and amino acid contents in tomato (Solanum lycopersicum).

MAIN CONCLUSION: Induced mutations in the SC-uORF of the tomato transcription factor gene SlbZIP1 by the CRISPR/Cas9 system led to the high accumulation of sugar and amino acid contents in tomato fruits. Tomato (Solanum lycopersicum) is one of the most popular and consumed vegetable crops in the world. Among important traits for tomato improvement such as yield, biotic and abiotic resistances, appearance, post-harvest shelf life and fruit quality, the last one seems to face more challenges because of its genetic and biochemical complexities. In this study, a dual-gRNAs CRISPR/Cas9 system was developed to induce targeted mutations in uORF regions of the SlbZIP1, a gene involved in the sucrose-induced repression of translation (SIRT) mechanism. Different induced mutations in the SlbZIP1-uORF region were identified at the T0 generation, stably transferred to the offspring, and no mutation was found at potential off-target sites. The induced mutations in the SlbZIP1-uORF region affected the transcription of SlbZIP1 and related genes in sugar and amino acid biosynthesis. Fruit component analysis showed significant increases in soluble solid, sugar and total amino acid contents in all SlbZIP1-uORF mutant lines. The accumulation of sour-tasting amino acids, including aspartic and glutamic acids, raised from 77 to 144%, while the accumulation of sweet-tasting amino acids such as alanine, glycine, proline, serine, and threonine increased from 14 to 107% in the mutant plants. Importantly, the potential SlbZIP1-uORF mutant lines with desirable fruit traits and no impaired effect on plant phenotype, growth and development were identified under the growth chamber condition. Our result indicates the potential utility of the CRISPR/Cas9 system for fruit quality improvement in tomato and other important crops.

Neoadjuvant treatment and survival outcomes by pathologic complete response in HER2-negative early breast cancers.

Background: The benefit of pathologic complete response (pCR) in early breast cancer (eBC) is not well described in the real-world setting. This study used the nationwide Flatiron Health electronic health record-derived deidentified database to describe treatment patterns and survival outcomes by pCR status after neoadjuvant therapy (NAT) in women with triple-negative or HR+/HER2- eBC. Materials & methods: Observational cohort study analyzing women with eBC who started NAT between 2011 and 2018. Results: 496 women were included in the study; of those, 16.1% achieved pCR, of which 35.7% were triple-negative and 6.1% were HR+/HER2- eBC. More women with triple-negative eBC (95.2%) were exclusively treated with chemotherapy-based NAT versus HR+/HER2- eBC (56.1%). In multivariate analyses from NAT start, not achieving pCR was associated with increased risk of death and progression. Conclusion: pCR status may be a reliable prognostic indicator for survival in these eBC subtypes in the real-world setting.

Response to treatment before surgery indicates better outcomes in breast cancer patients. To understand how well cancer treatments work, patients are compared on their overall survival. This measures the number of people in a study or treatment group who are still alive after a certain amount of time from when they were diagnosed or started treatment. Overall survival shows how well patients are doing in their cancer journey, but it takes time to understand how good treatments are when using this measure. In women with early-stage breast cancer, a quicker way to understand how well patients react to their treatment is called pathologic complete response (pCR). Some people have whole-body treatments such as chemotherapy before surgery (known as neoadjuvant treatment). For these patients, pCR may occur after neoadjuvant treatment, meaning all signs of cancer are gone when they have surgery. In real-life clinical settings, little research has been done to understand how pCR can measure breast cancer survival. In this study, the authors investigate whether women who had a pCR were more or less likely to have their cancer become worse or experience death than those who did not achieve pCR. The health records of 496 women diagnosed with early breast cancer over an eight-year period were assessed. The results show that women who did not have a pCR were more likely to have their cancer become worse or die. This means that pCR could be a better way than overall survival to identify which treatments work well in early breast cancer, and importantly, change the course of a patient's journey.

Real-world outcomes in metastatic HR+/HER2-, HER2+ and triple negative breast cancer after start of first-line therapy.

Aim: We evaluated outcomes of first-line (1L) treatment of metastatic breast cancer by biomarker subtype in the community setting over the last decade. Methods: Eligible patients (n = 1518) were female, ≥18 years, diagnosed with metastatic breast cancer 2010 or later, had documented HR+/HER2-, HER2+, or triple negative breast cancer (TNBC); and initiated 1L therapy. Kaplan-Meier and Cox methods were used to evaluate 1L real-world progression-free survival and overall survival from start of 1L. Results: TNBC was diagnosed at an earlier stage and had higher tumor grade at initial diagnosis. 1L real-world progression-free survival and overall survival from start of 1L were shorter for TNBC than HR+/HER2- or HER2+. Conclusion: Overall prognosis for patients with metastatic TNBC remains poor, and new therapies are needed to improve clinical outcomes.

What is this article about? This study looked at how well women with metastatic breast cancer did after starting treatment. It compared three groups. The first group had tumors that respond to hormone therapy. The second group had tumors that respond to treatment that works on a specific protein. A third group had tumors that don't respond to either of those ­ called triple negative. The study looked at women 18 and older who had metastatic breast cancer in 2010 or later. They had all been treated at a community oncology practice. We looked at how long it took for the cancer to get worse, and how long until patients died, for each of the three groups. What were the results? There were 1518 patients in the study. Most (62.5%) were in the group that responds to hormone therapy. The rest had tumors that respond to treatment that works on the specific protein (23.4%), or had triple negative tumors (14.1%). Patients with triple negative tumors were diagnosed earlier, but they had worse tumor characteristics. They also had shorter time until their cancer got worse, and they did not live as long, compared with the other groups. What do the results of the study mean? This builds on other studies by showing that, even in a modern era, outcomes are poor for patients with triple negative breast cancer. It shows that new treatments are needed for patients with triple negative breast cancer.

Association between inflammatory potential of diet and periodontitis disease risks: Results from a Korean population-based cohort study.

AIM: To examine the association between a pro-inflammatory diet, estimated using the energy-adjusted dietary inflammatory index (E-DII), and the risk of periodontitis. MATERIALS AND METHODS: Study subjects from the Korean Genome and Epidemiology Study Health Examinee (KoGES_HEXA) cohort were included for cross-sectional analysis (n = 168,378) using multivariate logistic regression and prospective analysis (n = 160,397) using Cox proportional hazard models respectively. DII and E-DII scores were calculated based on the intake reported on a validated semi-quantitative food frequency questionnaire (SQ-FFQ). RESULTS: Cox proportional hazard models revealed a significantly increased risk of incident periodontitis in individuals consuming high E-DII (more pro-inflammatory) diets in the total population (HRquartile4vs1 = 1.29; 95% CI: 1.13-1.48; ptrend <.001) and in both men (HRquartile4vs1 = 1.36; 95% CI: 1.07-1.73; ptrend = 0.02) and women (HRquartile4vs1 = 1.27; 95% CI: 1.08-1.50; ptrend = .002). The association remained significant even after excluding cases diagnosed early in the follow-up. In the cross-sectional analysis, a significant association was observed between the E-DII score and the prevalence of periodontitis among all study subjects (ORquartile4vs1 = 1.17; 95% CI: 1.03-1.34; ptrend = 0.01) and men (ORquartile4vs1 = 1.28; 95%CI: 1.01-1.63; ptrend <.001); however, the association did not reach statistical significance in women (ORquartile4vs1 = 1.13; 95% CI: 0.96-1.33; ptrend <.001). CONCLUSIONS: Findings from the current study support the hypothesis that diets with high pro-inflammatory potential increase the risk of periodontitis.

Lessons for Vietnam on the Use of Digital Technologies to Support Patient-Centered Care in Low- and Middle-Income Countries in the Asia-Pacific Region: Scoping Review.

BACKGROUND: A rapidly aging population, a shifting disease burden and the ongoing threat of infectious disease outbreaks pose major concerns for Vietnam's health care system. Health disparities are evident in many parts of the country, especially in rural areas, and the population faces inequitable access to patient-centered health care. Vietnam must therefore explore and implement advanced solutions to the provision of patient-centered care, with a view to reducing pressures on the health care system simultaneously. The use of digital health technologies (DHTs) may be one of these solutions. OBJECTIVE: This study aimed to identify the application of DHTs to support the provision of patient-centered care in low- and middle-income countries in the Asia-Pacific region (APR) and to draw lessons for Vietnam. METHODS: A scoping review was undertaken. Systematic searches of 7 databases were conducted in January 2022 to identify publications on DHTs and patient-centered care in the APR. Thematic analysis was conducted, and DHTs were classified using the National Institute for Health and Care Excellence evidence standards framework for DHTs (tiers A, B, and C). Reporting was in line with the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines. RESULTS: Of the 264 publications identified, 45 (17%) met the inclusion criteria. The majority of the DHTs were classified as tier C (15/33, 45%), followed by tier B (14/33, 42%) and tier A (4/33, 12%). At an individual level, DHTs increased accessibility of health care and health-related information, supported individuals in self-management, and led to improvements in clinical and quality-of-life outcomes. At a systems level, DHTs supported patient-centered outcomes by increasing efficiency, reducing strain on health care resources, and supporting patient-centered clinical practice. The most frequently reported enablers for the use of DHTs for patient-centered care included alignment of DHTs with users' individual needs, ease of use, availability of direct support from health care professionals, provision of technical support as well as user education and training, appropriate governance of privacy and security, and cross-sectorial collaboration. Common barriers included low user literacy and digital literacy, limited user access to DHT infrastructure, and a lack of policies and protocols to guide the implementation and use of DHTs. CONCLUSIONS: The use of DHTs is a viable option to increase equitable access to quality, patient-centered care across Vietnam and simultaneously reduce pressures on the health care system. Vietnam can take advantage of the lessons learned by other low- and middle-income countries in the APR when developing a national road map to digital health transformation. Recommendations that Vietnamese policy makers may consider include emphasizing stakeholder engagement, strengthening digital literacy, supporting the improvement of DHT infrastructure, increasing cross-sectorial collaboration, strengthening governance of cybersecurity, and leading the way in DHT uptake.

Land Use Influencing the Distribution of Pesticides in Surface Water: The Case of the Ma River and Its Tributaries in Thanh Hoa Province, Vietnam.

Pesticide residues are regularly found in surface water, which could be dangerous for freshwater ecosystems and biodiversity. Pesticides may enter waters through a variety of pathways, but runoff from irrigation or precipitation has the highest quantities. Previous studies analyzing the pesticides pollution or ecological risks of pesticides focused on few regions (e.g., European and United States), whereas analysis of pesticide pollution in Southeast Asia and especially in Vietnam is limited. This study presents an investigation of banned pesticides used across the range of land use in catchments of the Ma river and its tributaries in Thanh Hoa province, Vietnam. Applying principal component analysis (PCA), we investigated the relationship between specific pesticides and land use. Besides, cluster analysis (CA), the method of aggregating monitoring locations, was applied in this study to find spatial pattern of pesticides pollution. Due to their persistence and remobilization during floods and runoff, all ten banned pesticides-eight insecticides (aldrin/dieldrin, BHC, chlordane, endrin, heptachlor, lindane, malathion, and parathion) and two herbicides (paraquat, and 2,4D)-still remain in surface water and are not presumably influenced by the fraction of land use area in the catchments. Clustering results revealed that banned pesticides still occur in some areas. Site TH08 close to Le Mon industrial zone and TH18 in Thanh Hoa city have higher concentrations of banned pesticides than other sites due to their highly toxic and long-time existence in the environment. Overall, our study provides approach to investigate pesticides in surface water for a province in Vietnam that may be used for future ecotoxicological studies to enhance risk assessment for stream ecosystems.

[Évaluation de la gravité du cancer colorectal dépisté dans le contexte de la crise sanitaire liée au COVID19 en région Ile-de-France]. / Evaluation of the severity of screened colorectal cancer in the context of the health crisis linked to COVID19 in Ile-de-France region.

BACKGROUND: After the announcement in March 2020 of the COVID-19 pandemic, colorectal cancer (CRC) screening programs were suspended in several countries. Compared to the lesions detected during previous campaigns, this study aims to assess the severity of CRC detected during the 2020 screening campaign in Île-de-France, the French region most affected by the 1st wave of the pandemic. METHODS: The descriptive and etiological study included all faecal immunochemical test (FIT) results carried out between January 2017 and December 2020 on people aged 50-74, living in Île-de-France. First, the proportion of colonoscopies performed within one month (One-month-colo) following FIT; the yield of colonoscopy (proportion of colonoscopies with a neoplasm lesion among those performed) and CRC severity (TNM Classification, Level-0: T0/N0/M0, Level-1: T1/T2/N0/M0, Level-2: T3/T4/N0/M0; Level-3: T3/T4/N1/M0; Level-4: M1) were described in 2020 compared to previous campaigns (2017, 2018, and 2019). Subsequently, the link between the level of CRC severity and the predictive factors, including campaign year and time to colonoscopy, was analysed using polytomous multivariate regression. RESULTS: The one-month-colo (2017: 9.1% of 11,529 colonoscopies; 2018: 8.5% of 13,346; 2019: 5.7% of 7,881; 2020: 6.7% of 11,040; p < 0.001), the yield (65.2%, 64.1%, 62.4%, 60.8% respectively, p < 0.001) were significantly different between campaigns. The proportion of CRC level-4 (4.8% in 2017 (653 CRC); 7.6% in 2018 (674 CRC); 4.6% in 2019 (330 CRC) and 4.7% in 2020 (404 CRC); p < 0.29) was not significantly different between campaigns. The probability of having CRC with a high severity level was inversely related to the time to colonoscopy but not to the campaign year. Compared to patients having undergone colonoscopy within 30 days, the odds were significantly reduced by 60% in patients having undergone colonoscopy after 7 months (adjusted Odds-Ratio: 0.4 [0.3; 0.6]; p < 0.0001). CONCLUSIONS: The French indicators were certainly degraded before the first wave of the COVID-19. The delay in access to colonoscopy as well as its extension induced by the COVID-19 crisis had no impact in terms of cancer severity, due to a discriminatory approach prioritizing patients with evident symptoms.

Nanodiamond Solid-Phase Extraction and Triton X-114 Cloud Point Separation for Robust Fractionation and Shotgun Proteomics Analysis of the Human Serum Proteome.

Human serum is one of the most attractive specimens in biomarker research. However, its overcomplicated properties have hindered the analysis of low-abundance proteins by conventional mass spectrometry techniques. This work proposes an innovative strategy for utilizing nanodiamonds (NDs) in combination with Triton X-114 protein extraction to fractionate the crude serum to six pH-tuned fractions, simplifying the overall proteome and facilitating protein profiling with high efficiency. A total of 663 proteins are identified and evenly distributed among the fractions along with 39 FDA-approved biomarkers─a remarkable increase from the 230 proteins found in unfractionated crude serum. In the low-abundance protein section, 88 proteins with 7 FDA-approved biomarkers are detected─a marked increase from the 15 proteins (2 biomarkers) observed in the untreated sample. Notably, fractions at pH 11, derived from the aqueous phase of detergent separation, suggest potential applications in rapid and robust serum proteome analysis. Notably, by outlining the excellent properties of NDs for proteomic research, this work suggests a promising extraction protocol utilizing the great compatibility of NDs with streamlined serum proteomics and identifies potential avenues for future developments. Finally, we believe that this work not just improves shotgun proteomics but also opens up studies on the interaction between NDs and the human proteome. Data are available via ProteomeXchange with the identifier PXD029710.

Spin-Enhanced Lateral Flow Immunoassay for High-Sensitivity Detection of Nonstructural Protein NS1 Serotypes of the Dengue Virus.

Dengue fever is a global mosquito-borne viral infectious disease that has, in recent years, rapidly spread to almost all regions of the world. Lack of vaccination and directed treatment makes detection at the infection's early stages extremely important for disease prevention and clinical care. In this paper, we developed a rapid and highly sensitive dengue detection tool using a novel platform of diagnosis, called spin-enhanced lateral flow immunoassay (SELFIA) with a fluorescent nanodiamond (FND) as a reporter. Taking advantage of the unique magneto-optical properties of negatively charged nitrogen-vacancy centers in the FND, the SELFIA platform utilizes alternating electromagnetic fields to modulate signals from FND's fluorescence to provide sensitive and specific results. With sandwich SELFIA, we could efficiently detect all four dengue non-structural protein (NS1) serotypes (DV1, DV2, DV3, and DV4). The lowest detection concentration of the dengue NS1 antigens varied from 0.1 to 1.3 ng/mL, which is among the lowest limits of detection to date. The FND-based SELFIA technique is up to 500 and 5000 times more sensitive than carbon black and conventional gold nanoparticles, respectively. By using different anti-NS1 antibodies, we could differentiate the NS1 antigen serotypes contained in the tested samples via three simultaneous assays. Proposed SELFIA allows for both qualitative and quantitative differentiation between different NS1 protein serotypes, which will assist in the development of a highly sensitive and specific detection platform for dengue screening that has the potential to detect the disease at its early stages, especially in high-risk and limited-resource areas.

Prediabetes and insulin resistance in a population of patients with heart failure and reduced or preserved ejection fraction but without diabetes, overweight or hypertension.

BACKGROUND: The relationships between glucose abnormalities, insulin resistance (IR) and heart failure (HF) are unclear, especially regarding to the HF type, i.e., HF with reduced (HFrEF) or preserved (HFpEF) ejection fraction. Overweight, diabetes and hypertension are potential contributors to IR in persons with HF. This study aimed to evaluate the prevalence of prediabetes and IR in a population of Vietnamese patients with HFrEF or HFpEF but no overweight, diabetes or hypertension, in comparison with healthy controls, and the relation between prediabetes or IR and HF severity. METHODS: We conducted a prospective cross-sectional observational study in 190 non-overweight normotensive HF patients (114 with HFrEF and 76 with HFpEF, 92.6% were ischemic HF, mean age was 70.1 years, mean BMI 19.7 kg/m2) without diabetes (neither known diabetes nor newly diagnosed by OGTT) and 95 healthy individuals (controls). Prediabetes was defined using 2006 WHO criteria. Glucose and insulin levels were measured fasting and 2 h after glucose challenge. IR was assessed using HOMA-IR and several other indexes. RESULTS: Compared to controls, HF patients had a higher prevalence of prediabetes (63.2% vs 22.1%) and IR (according to HOMA-IR, 55.3% vs 26.3%), higher HOMA-IR, insulin/glucose ratio after glucose and FIRI, and lower ISIT0 and ISIT120 (< 0.0001 for all comparisons), with no difference for body weight, waist circumference, blood pressure and lipid parameters. Prediabetes was more prevalent (69.3% vs 53.9%, p = 0.03) and HOMA-IR was higher (p < 0.0001) in patients with HFrEF than with HFpEF. Among both HFrEF and HFpEF patients, those with prediabetes or IR had a more severe HF (higher NYHA functional class and NT-proBNP levels, lower ejection fraction; p = 0.04-< 0.0001) than their normoglycemic or non-insulinresistant counterparts, with no difference for blood pressure and lipid parameters. CONCLUSION: In non-diabetic non-overweight normotensive patients with HF, the prevalence of prediabetes is higher with some trend to more severe IR in those with HFrEF than in those with HFpEF. Both prediabetes and IR are associated with a more severe HF. The present data support HF as a culprit for IR. Intervention strategies should be proposed to HF patients with prediabetes aiming to reduce the risk of incident diabetes. Studies should be designed to test whether such strategies may translate into an improvement of further HF-related outcomes.

Overall survival in the real-world and clinical trials: a case study validating external controls in advanced melanoma.

Aims: We assessed the suitability of real-world data (RWD) as an external control for analysis of overall survival (OS) compared with clinical trial data (CTD) in advanced melanoma. Methods: OS among adults receiving ipilimumab for advanced melanoma was compared between trials (CTD group) and the Flatiron Health database (RWD group) using Cox models. Adjusted analyses accounted for differences in baseline factors; missing data were addressed through multiple imputation. Results: After adjusting for baseline factors and accounting for missingness, OS was similar in the CTD (n = 241) versus RWD groups (n = 816; hazard ratio: 0.98; 95% CI: 0.75-1.26). Conclusion: Flatiron Health data is suitable to construct external control groups for OS in advanced melanoma trials after adjusting for baseline factors and missing data.

Clinical trials are the gold standard for measuring the efficacy and safety of new treatments. Comparisons between clinical trials and external controls drawn from real-world data are potentially valuable ­ especially when randomized trials are not available or feasible ­ but carry important risks of bias stemming from differences across populations, care settings and measurement of patient characteristics and outcomes. As a case study, we assessed the suitability of a particular real-world database (the Flatiron Health Database) for analyzing overall survival among patients in clinical trials of treatments for metastatic melanoma. Challenges included differences in patient baseline prognostic factors across populations, including high proportions with missing information in real-world data. After accounting for these differences, we observed similar survival between patients receiving ipilimumab monotherapy in clinical trials and in real-world data. We conclude that real-world external controls can be suitable for metastatic melanoma.

Adverse events and clinical outcomes in patients treated with PD-(L)1 blockade for advanced non-small-cell lung cancer.

Aims: To describe, in patients with advanced/metastatic non-small-cell lung cancer, the relationship between baseline immunosuppressive drug (ISD)/corticosteroid (CS) use, as well as the incidence of mild/moderate adverse events (AEs), and the clinical effectiveness of PD (L)-1 blockade. Patients & methods: This was a retrospective cohort study of patients with no evidence (n = 131) or positive evidence (n = 269) of ISD/CS use. Results: Duration of treatment, time to next treatment, progression-free survival and overall survival were significantly reduced for patients with evidence of prior ISD/CS use. Occurrence of mild/moderate AEs did not affect any clinical outcomes. Conclusion: Prior ISD/CS use was associated with a poorer prognosis in advanced/metastatic non-small-cell lung cancer patients treated with PD-(L)1 inhibitors, but the occurrence of AEs had no effect.

What is the article about? Patients with advanced/metastatic non-small-cell lung cancer (aNSCLC) are often treated with a class of drugs known as checkpoint inhibitors. There have been previous reports that treatment with corticosteroids and other drugs that suppress the immune system in the period leading up to treatment with checkpoint inhibitors may result in poorer outcomes, but most of these reports focus on serious adverse events leading to hospitalizations or emergency room visits that result from treatment. This study aimed to determine whether treatment with corticosteroids in these patients had any impact on the occurrence of mild or moderate adverse events and long-term treatment outcomes. What were the results? By looking back at deidentified medical insurance claims from patients with aNSCLC, we found that patients who were treated with corticosteroids or other immunosuppressive drugs (vs those who did not receive these drugs) in the months leading up to treatment with checkpoint inhibitors had poorer treatment outcomes (e.g., shorter overall survival). What do the results of the study mean? This study investigated the real-world outcomes in aNSCLC patients treated with checkpoint inhibitors and found that the use of corticosteroids or other immunosuppressive drugs may have an adverse effect. However, we are unable to rule out the possibility that there was an underlying difference between these two sets of patients that caused the difference in treatment outcomes. Further studies with larger sample sizes are needed.

Dynamic multivariate analysis for pollution assessment and river habitat conservation in the Vietnamese La Buong watershed.

Analysis of temporal patterns of high-dimensional time-series water quality data is essential for pollution management worldwide. This study has applied dynamic factor analysis (DFA) and cluster analysis (CA) to analyze time-series water quality data monitored at the five stations installed along the La Buong river in Southern Vietnam. Application of the DFA identified two types of temporal patterns, one of the run-off driven parameters (total suspended solid (TSS), turbidity, and iron) and the other of diffuse source pollution. The association of the variables like BOD5 and COD at most stations to the run-off-driven parameters revealed their sharing of drivers. On the contrary, separating variables like phosphate (PO43) at the three upstream stations from the run-off patterns suggested their local point-source origin. The DFA-derived factors were later used in the time-point CA to explore the seasonality of water quality parameters and their pollution intensities compared to regulatory levels. The result suggested intensification in wet season of Fe, TSS, BOD5, and COD concentrations at most sites, which are unobservable in run-off detached parameters like reactive nitrogen, phosphate (PO43-), and E. coli. These findings generated robust insights to support water quality management for river habitat conservation.

One-pot synthesis of manganese oxide/graphene composites via a plasma-enhanced electrochemical exfoliation process for supercapacitors.

In this work, a feasible one-pot approach to synthesize manganese oxide/graphene composites, the so-called plasma-enhanced electrochemical exfoliation process (PE3P), has been developed. Herein, a composite of graphene decorated with manganese oxide nanoparticles was prepared via PE3P from a KMnO4 solution and graphite electrode under a voltage of 70 V in an ambient environment. By controlling the initial KMnO4 concentration, we obtained distinct MnO2/graphene samples. The prepared samples were characterized by scanning electron microscopy, transmission electron microscopy, x-ray diffraction, x-ray photoelectron spectroscopy, and Raman spectroscopy. The electrochemical measurements of the MnO2/graphene composites revealed that the specific capacitance of the samples is approximately 320 F g-1 at a scan rate of 10 mV s-1, which is comparably very high for manganese oxide/carbon-based supercapacitor electrode materials. Considering the simple, low-cost, one-step and environmentally friendly preparation, our approach has the potential to be used for the fabrication of MnO2/graphene composites as the electrode materials of supercapacitors.

E2~Ub conjugates regulate the kinase activity of Shigella effector OspG during pathogenesis.

Pathogenic bacteria introduce effector proteins directly into the cytosol of eukaryotic cells to promote invasion and colonization. OspG, a Shigella spp. effector kinase, plays a role in this process by helping to suppress the host inflammatory response. OspG has been reported to bind host E2 ubiquitin-conjugating enzymes activated with ubiquitin (E2~Ub), a key enzyme complex in ubiquitin transfer pathways. A co-crystal structure of the OspG/UbcH5c~Ub complex reveals that complex formation has important ramifications for the activity of both OspG and the UbcH5c~Ub conjugate. OspG is a minimal kinase domain containing only essential elements required for catalysis. UbcH5c~Ub binding stabilizes an active conformation of the kinase, greatly enhancing OspG kinase activity. In contrast, interaction with OspG stabilizes an extended, less reactive form of UbcH5c~Ub. Recognizing conserved E2 features, OspG can interact with at least ten distinct human E2s~Ub. Mouse oral infection studies indicate that E2~Ub conjugates act as novel regulators of OspG effector kinase function in eukaryotic host cells.