Nevin Manimala

J Natl Cancer Inst. 2021 Jul 12:djab128. doi: 10.1093/jnci/djab128. Online ahead of print.

ABSTRACT

BACKGROUND: Although an immunosuppressive tumor microenvironment (TME) is key for tumor progression, the molecular characteristics associated with the immunosuppressive TME remain unknown in triple-negative breast cancer (TNBC). Our previous functional proteomic study of TNBC tumors identified that C-JUN N-terminal kinase (JNK) pathway-related molecules were enriched in a cluster associated with the inflammatory pathway. However, the role of the JNK pathway in the TNBC TME is still unclear.

METHODS: Transcriptomic analysis was conducted using The Cancer Genome Atlas (TCGA) datasets. The effect of JNK-IN-8, a covalent pan-JNK inhibitor, on TNBC tumor growth, lung metastasis, and the TME was measured in TNBC syngeneic mouse models (n = 13 per group). Tumor (n = 43) or serum (n = 46) samples from TNBC patients were analyzed using multiplex immunohistochemistry or Luminex assay. All statistical tests were 2-sided.

RESULTS: CIBERSORT analysis revealed that TNBC patients with high pJNK level (n = 47) had more regulatory T cell (Treg) infiltration than those with low pJNK level (n = 47) (P = .02). Inhibition of JNK signaling statistically significantly reduced tumor growth (P < .001) and tumor-infiltrating Tregs (P = .02) while increasing the infiltration of CD8+ T cells in TNBC mouse models through the reduction of C-C motif ligand 2 (CCL2). Tumor-associated macrophages (TAMs) were the predominant cells secreting CCL2, and inhibition of JNK signaling reduced CCL2 secretion of human primary macrophages. Moreover, in patients with TNBC (n = 43), those with high levels of CCL2+ TAMs had more Treg and less CD8+ T cell infiltration (P = .04), and serum CCL2 level was associated with poor overall survival (hazard ratio = 2.65, 95% confidence interval = 1.29 to 5.44; P = .008) in TNBC patients (n = 46).

CONCLUSIONS: The JNK/C-JUN/CCL2 axis contributes to TNBC aggressiveness via forming an immunosuppressive TME and can offer novel therapeutic strategies for TNBC.

PMID:34250544 | DOI:10.1093/jnci/djab128

J Infect Dis. 2021 Jul 12:jiab198. doi: 10.1093/infdis/jiab198. Online ahead of print.

NO ABSTRACT

PMID:34250540 | DOI:10.1093/infdis/jiab198

Lancet Microbe. 2021 Jul 6. doi: 10.1016/S2666-5247(21)00146-4. Online ahead of print.

ABSTRACT

BACKGROUND: We hypothesised that host-response biomarkers of viral infections might contribute to early identification of individuals infected with SARS-CoV-2, which is critical to breaking the chains of transmission. We aimed to evaluate the diagnostic accuracy of existing candidate whole-blood transcriptomic signatures for viral infection to predict positivity of nasopharyngeal SARS-CoV-2 PCR testing.

METHODS: We did a nested case-control diagnostic accuracy study among a prospective cohort of health-care workers (aged ≥18 years) at St Bartholomew’s Hospital (London, UK) undergoing weekly blood and nasopharyngeal swab sampling for whole-blood RNA sequencing and SARS-CoV-2 PCR testing, when fit to attend work. We identified candidate blood transcriptomic signatures for viral infection through a systematic literature search. We searched MEDLINE for articles published between database inception and Oct 12, 2020, using comprehensive MeSH and keyword terms for “viral infection”, “transcriptome”, “biomarker”, and “blood”. We reconstructed signature scores in blood RNA sequencing data and evaluated their diagnostic accuracy for contemporaneous SARS-CoV-2 infection, compared with the gold standard of SARS-CoV-2 PCR testing, by quantifying the area under the receiver operating characteristic curve (AUROC), sensitivities, and specificities at a standardised Z score of at least 2 based on the distribution of signature scores in test-negative controls. We used pairwise DeLong tests compared with the most discriminating signature to identify the subset of best performing biomarkers. We evaluated associations between signature expression, viral load (using PCR cycle thresholds), and symptom status visually and using Spearman rank correlation. The primary outcome was the AUROC for discriminating between samples from participants who tested negative throughout the study (test-negative controls) and samples from participants with PCR-confirmed SARS-CoV-2 infection (test-positive participants) during their first week of PCR positivity.

FINDINGS: We identified 20 candidate blood transcriptomic signatures of viral infection from 18 studies and evaluated their accuracy among 169 blood RNA samples from 96 participants over 24 weeks. Participants were recruited between March 23 and March 31, 2020. 114 samples were from 41 participants with SARS-CoV-2 infection, and 55 samples were from 55 test-negative controls. The median age of participants was 36 years (IQR 27-47) and 69 (72%) of 96 were women. Signatures had little overlap of component genes, but were mostly correlated as components of type I interferon responses. A single blood transcript for IFI27 provided the highest accuracy for discriminating between test-negative controls and test-positive individuals at the time of their first positive SARS-CoV-2 PCR result, with AUROC of 0·95 (95% CI 0·91-0·99), sensitivity 0·84 (0·70-0·93), and specificity 0·95 (0·85-0·98) at a predefined threshold (Z score >2). The transcript performed equally well in individuals with and without symptoms. Three other candidate signatures (including two to 48 transcripts) had statistically equivalent discrimination to IFI27 (AUROCs 0·91-0·95).

INTERPRETATION: Our findings support further urgent evaluation and development of blood IFI27 transcripts as a biomarker for early phase SARS-CoV-2 infection for screening individuals at high risk of infection, such as contacts of index cases, to facilitate early case isolation and early use of antiviral treatments as they emerge.

FUNDING: Barts Charity, Wellcome Trust, and National Institute of Health Research.

PMID:34250515 | PMC:PMC8260104 | DOI:10.1016/S2666-5247(21)00146-4

Affect Sci. 2021 Jul 7:1-10. doi: 10.1007/s42761-021-00051-z. Online ahead of print.

ABSTRACT

Most work to date in psychology and related sciences has examined simple, unidirectional causal processes of emotion affecting socio-political context or vice versa. In this classic, mechanistic view of science, each empirical observation stands on its own as a piece of some grander, not yet understandable, puzzle of nature. There have been repeated calls to eschew classic approaches in favor of systems meta-theory in psychology and related sciences. In this paper, we join these calls by arguing that systems meta-theory can better enable the study of emotions in socio-political contexts. We offer a brief primer on systems meta-theory, delineating three key beneficial features: multi-leveled, complex, and dynamic. Viewing emotion as a system of systems-within the person, their relationships (to others), and within the world (locally and globally)-enables fresh theory, method, and statistical analysis well suited to the study of emotion in a socio-political context.

PMID:34250508 | PMC:PMC8260573 | DOI:10.1007/s42761-021-00051-z

Gynecol Reprod Health. 2021;5(1):1488.

ABSTRACT

BACKGROUND: Pregestational diabetes complicates one million pregnancies in the United States and is associated with placental dysfunction. Placental dysfunction can manifest as stillbirth, spontaneous abortions, fetal growth restriction, and preeclampsia in the mother. However, the underlying mechanisms of placental dysfunction are not well understood.

OBJECTIVE: We hypothesize that maternal hyperglycemia disrupts cellular processes important for normal vascular development and function.

STUDY DESIGN: Hyperglycemia, defined as a non-fasting glucose concentration of >250 mg/dL was induced in eight-week-old female CD1 mice by injecting a one-time intraperitoneal dose of 150mg/kg streptozotocin. Control mice received an equal volume of normal saline. Hyperglycemic and control females were mated with CD-1 males. At Embryonic Day 17.5, the pregnant mice were euthanized. Sixty-eight placentas were harvested from the six euglycemic dams and twenty-six placentas were harvested from three hyperglycemic dams. RNA was extracted from homogenized placental tissue (N=12/group; 2-4 placentas per litter of each group). Total RNA was prepared and sequenced. Differentially expressed genes that were >2-fold change was considered significant. Placentas (9-20/group) were fixed in paraffin wax and sectioned at 6 μm. Cross-sectional areas of placental zones were evaluated using slides stained for hematoxylin and eosin, glycogen, collagen, proliferation and apoptosis. Quantification of staining intensity and percent positive nuclei was done using Leica Image Hub Data software. Data were compared between the control and experimental group using t-tests. Values of p < 0.05 were considered to be statistically significant.

RESULTS: The average maternal blood glucose concentrations for control and diabetic dams were 112+/-24 and 473+/-47 respectively (p<0.0001). A higher rate of resorptions was noted in the hyperglycemia exposed placentas compared to euglycemic exposed placentas (24% vs 7%; p=0.04). A total of 24 RNA libraries (12/group) were prepared. Placentas from hyperglycemic pregnancies exhibited 1374 differentially expressed genes (DEGs). The 10 most significantly differentially expressed genes are Filip 1, Prom 2, Fam 78a, Pde4d, Pou3f1, Kcnk5, Dusp4, Cxcr4, Slc6a4 and D430019H16Rik. Their corresponding biologic functions are related to chemotaxis, ossification, cellular and vascular development. Histologically, we found that hyperglycemia exposed placentas demonstrated increased proliferation, apoptosis, and glycogen content and decreased collagen deposition.

CONCLUSION: There was a higher rate of resorptions in the pregnancies of hyperglycemic dams. Pregestational diabetes resulted in significant changes in placental morphology, including increased glycogen content in the spongiotrophoblast, decreased collagen deposition, increased apoptosis and proliferation in the junction zone. Maternal diabetes causes widespread disruption in multiple cellular processes important for normal vascular development and sets the platform for placenta dysfunction.

PMID:34250501 | PMC:PMC8270392

Crit Care Explor. 2021 Jul 6;3(7):e0457. doi: 10.1097/CCE.0000000000000457. eCollection 2021 Jul.

ABSTRACT

Acute respiratory distress syndrome is underrecognized in the ICU, but it remains uncertain if acute respiratory distress syndrome recognition affects evidence-based acute respiratory distress syndrome care in the modern era. We sought to determine the rate of clinician-recognized acute respiratory distress syndrome in an academic medical ICU and understand how clinician-recognized-acute respiratory distress syndrome affects clinical care and patient-centered outcomes.

DESIGN: Observational cohort study.

SETTING: Single medical ICU at an academic tertiary-care hospital.

PATIENTS: Nine hundred seventy-seven critically ill adults (381 with expert-adjudicated acute respiratory distress syndrome) enrolled from 2006 to 2015.

INTERVENTIONS: Clinician-recognized-acute respiratory distress syndrome was identified using an electronic keyword search of clinical notes in the electronic health record. We assessed the classification performance of clinician-recognized acute respiratory distress syndrome for identifying expert-adjudicated acute respiratory distress syndrome. We also compared differences in ventilator settings, diuretic prescriptions, and cumulative fluid balance between clinician-recognized acute respiratory distress syndrome and unrecognized acute respiratory distress syndrome.

MEASUREMENTS AND MAIN RESULTS: Overall, clinician-recognized-acute respiratory distress syndrome had a sensitivity of 47.5%, specificity 91.1%, positive predictive value 77.4%, and negative predictive value 73.1% for expert-adjudicated acute respiratory distress syndrome. Among the 381 expert-adjudicated acute respiratory distress syndrome cases, we did not observe any differences in ventilator tidal volumes between clinician-recognized-acute respiratory distress syndrome and unrecognized acute respiratory distress syndrome, but clinician-recognized-acute respiratory distress syndrome patients had a more negative cumulative fluid balance (mean difference, -781 mL; 95% CI, [-1,846 to +283]) and were more likely to receive diuretics (49.3% vs 35.7%, p = 0.02). There were no differences in mortality, ICU length of stay, or ventilator-free days.

CONCLUSIONS: Acute respiratory distress syndrome recognition was low in this single-center study. Although acute respiratory distress syndrome recognition was not associated with lower ventilator volumes, it was associated with differences in behaviors related to fluid management. These findings have implications for the design of future studies promoting evidence-based acute respiratory distress syndrome interventions in the ICU.

PMID:34250497 | PMC:PMC8263322 | DOI:10.1097/CCE.0000000000000457

Nurs Open. 2021 Jul 11. doi: 10.1002/nop2.985. Online ahead of print.

ABSTRACT

AIMS: To develop a competency scale for operating room nurses and test its reliability and validity.

BACKGROUND: The existing Chinese Registered Nurse Competency Scale and the core competency scale for operating room nurses developed abroad cannot fully meet the capacity needs of Chinese operating room nurses.

METHODS: The scale was developed based on the results of qualitative interview and the Delphi method. Ten experts were selected for expert consultation, and 300 operating room nurses were recruited by convenience sampling for a cross-sectional survey to test the reliability and validity of instrument.The reliability and validity of the scale was assessed based on internal consistency reliability, test-retest reliability and confirmatory factor analysis. Data collection was conducted between March to July, 2015.

RESULTS: An initial scale with 42 items was confirmed, and 36 items remained. The internal consistency Cronbach’s α was 0.97 for the overall scale and 0.88-0.94 for the subscales. The retest reliability ranged from 0.55-0.96. Five factors were extracted by exploratory factor analysis, and they explained 66% of the total variance. The fitting indices of the confirmatory factor analysis were as follows: χ2/df = 3.47, CFI = 0.83, TLI = 0.81, SRMR = 0.06 and RMSEA = 0.09.

CONCLUSIONS: The core competency scale for operating room nurses with 5 components and 36 items had acceptable reliability and validity. The scale could continue to be optimized in the future.

PMID:34247455 | DOI:10.1002/nop2.985

Health Expect. 2021 Jul 10. doi: 10.1111/hex.13306. Online ahead of print.

ABSTRACT

BACKGROUND: Patient participation is essential for achieving high-quality care and positive outcomes, especially among patients with multimorbidity, which is a major challenge for health care due to high prevalence, care complexity and impact on patients’ lives.

OBJECTIVE: To explore the patient participation related to their own care among patients with multimorbidity in primary health-care settings.

METHODS: A cross-sectional survey was conducted among adult multimorbid patients who visited primary health-care facilities. The key instrument used was the Participation in Rehabilitation Questionnaire. Data representing 125 patients were analysed using various statistical methods.

RESULTS: The respondents generally felt patient participation to be important, yet provided highly varying accounts regarding the extent to which it was realized by professionals. Information and knowledge and Respect and encouragement were considered the most important and best implemented subcategories of participation. Several patient-related factors had a statistically significant effect on patient perceptions of participation for all subcategories and as explanatory factors for perceptions of total participation in univariate models. Most patients reported active participation in health-care communication, positively associated with patient activation and adherence. Gender, perceived health, patient activation and active participation were explanatory factors for total importance of participation in multivariate models, while patient activation was retained for realization of participation.

CONCLUSIONS: Multimorbid patients require individualized care that promotes participation and active communication; this approach may further improve patient activation and adherence. Poor perceived health and functional ability seemed to be related to worse perceptions of participation.

PATIENT AND PUBLIC INVOLVEMENT: The study topic importance was based on the patients’ experiences in author’s previous research and the need to develop patient-centred care.

PMID:34247439 | DOI:10.1111/hex.13306

Helicobacter. 2021 Jul 10:e12830. doi: 10.1111/hel.12830. Online ahead of print.

ABSTRACT

BACKGROUND: Vonoprazan fumarate is a novel potassium-competitive acid blocker more effective in suppressing acid production than proton pump inhibitors (PPIs) and when combined with antibiotics has been used to eradicate Helicobacter pylori (H. pylori) infection. However, it has not yet been examined in an Australian setting. This study aimed to report on the efficacy and safety of vonoprazan-containing antibiotic combination therapies in the eradication of H. pylori.

METHODS: A single-center, exploratory, clinical review of patients 18 years or over, positive for H. pylori on Urea Breath Test (UBT), and/or histopathology who underwent a 10-day treatment of combination antibiotics plus vonoprazan between January 2017 and September 2019 was conducted. Eleven different combinations of antibiotics that included 2-5 different antibiotics predominantly amoxicillin, rifabutin, levofloxacin, furazolidone, nitazoxanide, and tetracycline were included. The eradication success was based on negative UBT results and/or histopathology results after the treatment. Descriptive statistics were summarized.

RESULTS: One hundred and fifty-three patients (Female n = 74, 48%) with a positive for H. pylori were treated with vonoprazan-containing antibiotic combination therapy during the study period. Of the 153 patients, 48 (31%) had previously failed a PPI-based H. pylori treatment. Follow-up was available for 66/153 (43%) patients. In those who completed follow-up, overall eradication was achieved in 97% (64/66) of patients. In the subgroup of patients treated for the first time, eradication was achieved in 100% (44/44). In those who had failed prior, non-vonoprazan-containing treatment, eradication was achieved in 91% (20/22) of patients.

CONCLUSIONS: Vonoprazan-containing antibiotic therapy is an effective H. pylori eradication treatment. It is capable of achieving 100% efficacy in patients treated for the first time and even 91% efficacy in patients with previous eradication failure. Subsequent studies utilizing a factorial design will be needed to optimize each regimen as most regimens contained more than two antibiotics.

PMID:34247436 | DOI:10.1111/hel.12830

Andrologia. 2021 Jul 11:e14180. doi: 10.1111/and.14180. Online ahead of print.

ABSTRACT

Our study objective was to assess the effect of various sperm DNA fragmentation levels on clinical intracytoplasmic sperm injection outcome. This retrospective study included 392 patients who underwent ICSI and performed sperm DNA fragmentation testing before the procedure. Based on sperm DNA fragmentation cut-off values, the patients were differentiated into 3 groups as <20%, 20%-30% and >30%. According to the female status, patients were differentiated into favourable group (n = 259) with female age <35 years and anti-Mullerian hormone level ≥7.1 pmol/L; and unfavourable group (n = 133) with female age ≥35 years and anti-Mullerian hormone level ≤7.1 pmol/L. The patient’s medical records were reviewed, and patient’s demographic, laboratory data including semen analysis, sperm DNA fragmentation determined by means of sperm chromatin dispersion, hormonal profile and data regarding intracytoplasmic sperm injection cycle were collected. This cohort reported that the clinical reproductive outcomes of intracytoplasmic sperm injection showed no statistical significance with increase sperm DNA fragmentation levels. In sperm DNA fragmentation above 30%, favourable females had significantly higher clinical pregnancy rate and live birth rate than unfavourable females, while fertilisation rate and miscarriage rate showed no significance between the subgroups. High sperm DNA fragmentation is linked to poor semen parameters.

PMID:34247427 | DOI:10.1111/and.14180