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The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic has posed multiple challenges to global public health. Clinical features and sequela of SARS-CoV-2 infection include long-term and short-term complications often clinically indistinguishable from bacterial sepsis and acute lung infection. Post-hoc studies of previous SARS outbreaks postulate secondary bacterial infections with microbial dysbiosis. Oral microbial dysbiosis, particularly the altered proportion of Firmicutes and Proteobacteria, observed in other respiratory virus infection, like influenza, has shown to be associated with increased morbidity and mortality. Oropharynx and lung share similar kinds of bacterial species. We hypothesized that alteration in the Human Oropharyngeal Microbiome in SARS-CoV-2 patients can be a clinical indicator of bacterial infection related complications. We made a longitudinal comparison of oropharyngeal microbiome of 20 SARS-CoV-2 patients over a period of 30 days; at three time points, with a 15 days interval; contrasting them with a matched group of 10 healthy controls. Present observation indicates that posterior segment of the oropharyngeal microbiome is a key reservoir for bacteria causing pneumonia and chronic lung infection on SARS-CoV-2 infection. Oropharyngeal microbiome is indeed altered and its α-diversity decreases, indicating reduced stability, in all SARS-CoV-2 positive individuals right at Day-1; i.e. within ~24 h of post clinical diagnosis. The dysbiosis persists long-term (30 days) irrespective of viral clearance and/or administration of antibiotics. There is a severe depletion of commensal bacteria phyla like Firmicutes among the patients and that depletion is compensated by higher proportion of bacteria associated with sepsis and severe lung infection from phyla Proteobacteria. We also found elevated proportions of certain genus that have previously been shown to be causal for lung pneumonia in studies of model organisms and human autopsies’ including Stenotrophomonas, Acenetobactor, Enterobactor, Klebsiella and Chryseobacterium that were to be elevated among the cases. We also show that responses to the antibiotics (Azithromycin and Doxycycline) are not uniform for all individuals.

Patients with differentiated thyroid cancer can often be treated with postoperative radioiodine (also called radioiodine ablation) after total thyroidectomy. The IoN trial was designed to assess whether recurrence-free survival was non-inferior after no ablation compared with ablation in patients with low-risk differentiated thyroid cancer. IoN was a multicentre, non-inferiority, phase 3 randomised trial conducted at 33 UK cancer centres. Eligible patients had complete (R0) resection following total thyroidectomy; stage pT1, pT2, pT3 (according to Tumour, Node, Metastasis staging version 7 [TNM7]), or pT3a (according to TNM8) disease; and N0, Nx, or N1a disease. Participants were randomly assigned (1:1) by minimisation, using a central electronic system, to have either 1·1 GBq ablation or no ablation, following thyroidectomy. Stratification factors were centre, age, T stage, and nodal status. Patients had annual neck ultrasound scans and 6-monthly serum thyroglobulin measurements. The primary endpoint was 5-year recurrence-free survival, defined by the absence of locoregional recurrent or persistent structural disease, distant metastases, or death from thyroid cancer. Non-inferiority was assessed with a margin of 5 percentage points. Per-protocol and intention-to-treat (ITT) analyses were done for the primary endpoint, and safety was analysed in the per-protocol population. The trial is registered with ClinicalTrials.gov (NCT01398085), ISRCTN (ISRCTN80416929), and EUDRACT (2011–000144–21), and is still in active follow-up. We recruited 504 patients (including 390 [77%] female patients and 114 [23%] male patients) between June 26, 2012 and March 18, 2020 and randomly assigned 251 to receive no ablation and 253 to receive ablation (ITT population). 249 patients in the no ablation group did not have ablation and 231 in the ablation group had ablation (per-protocol population). Median follow-up was 6·8 years (IQR 5·6–8·6) in the no ablation group and 6·6 years (4·8–8·5) in the ablation group; 17 recurrences (eight in the no ablation group and nine in the ablation group; ITT population) occurred during follow-up. 5-year recurrence-free rates were 97·9% (95% CI 96·1–99·7) in the no ablation group versus 96·3% (93·9–98·7) in the ablation group in the ITT analysis, and 97·9% (96·1–99·7) versus 96·9% (94·7–99·1) in the per-protocol analysis. The 5-year absolute risk difference was 0·5 percentage points (95% CI –2·2 to 3·2, pnon-inferiority=0·033; ITT analysis), showing that non-inferiority was reached. The observed recurrence rate was higher among patients with pT3 or pT3a tumours (four [9%] of 46 patients overall with pT3 or pT3a tumours vs 13 [3%] of 458 with pT1 or pT2 tumours), or N1a tumours (six [13%] of 47 with N1a vs 11 [2%] of 457 with N0 or Nx), but they were similar among those who did not receive ablation. Adverse events were similar between the groups, the most common being fatigue (63 [25%] of 249 in the no ablation group vs 65 [28%] of 231 in the ablation group), lethargy (34 [14%] vs 32 [14%]), and dry mouth (24 [10%] vs 21 [9%]), and there were no treatment-related deaths. The IoN trial shows that ablation (or postoperative radioiodine) can be avoided for patients with pT1, pT2, and N0 or Nx tumours with no adverse features. Many patients with low-risk differentiated thyroid cancer worldwide can safely avoid postoperative radioiodine and its related hospitalisation and side-effects, which in turn results in lower health-care costs. Cancer Research UK.

PARTNER is a prospective, phase II–III, randomized controlled clinical trial that recruited patients with triple-negative breast cancer 1 , 2 , who were germline  BRCA 1 and BRCA2 wild type 3 . Here we report the results of the trial. Patients ( n  = 559) were randomized on a 1:1 basis to receive neoadjuvant carboplatin–paclitaxel with or without 150 mg olaparib twice daily, on days 3 to 14, of each of four cycles (gap schedule olaparib, research arm) followed by three cycles of anthracycline-based chemotherapy before surgery. The primary end point was pathologic complete response (pCR) 4 , and secondary end points included event-free survival (EFS) and overall survival (OS) 5 . pCR was achieved in 51% of patients in the research arm and 52% in the control arm ( P  = 0.753). Estimated EFS at 36 months in the research and control arms was 80% and 79% (log-rank P  > 0.9), respectively; OS was 90% and 87.2% (log-rank P  = 0.8), respectively. In patients with pCR, estimated EFS at 36 months was 90%, and in those with non-pCR it was 70% (log-rank P  < 0.001), and OS was 96% and 83% (log-rank P  < 0.001), respectively. Neoadjuvant olaparib did not improve pCR rates, EFS or OS when added to carboplatin–paclitaxel and anthracycline-based chemotherapy in patients with triple-negative breast cancer who were germline BRCA1 and BRCA2 wild type. ClinicalTrials.gov ID: NCT03150576 . A study details the results of the PARTNER trial, a prospective, randomized controlled trial of the use of neoadjuvant olaparib with carboplatin–paclitaxel chemotherapy in patients with triple-negative breast cancer who were germline BRCA1 and BRCA2  wild type.

PARTNER is a prospective, phase II-III, randomised controlled clinical trial, which recruited patients with Triple Negative Breast Cancer (TNBC) , who were gBRCA wild type (gBRCAwt) . Patients (n=559) were randomised on a 1:1 basis to neoadjuvant carboplatin with paclitaxel +/- olaparib 150mg twice daily, days 3 to 14, for 4 cycles (gap schedule olaparib, research arm) followed by 3 cycles of anthracycline chemotherapy before surgery. The primary endpoint was pathological complete response (pCR) , and secondary endpoints included event-free survival (EFS), and overall survival (OS) . pCR was achieved in 51% in the research arm and 52% in the control arm (p=0.753). Estimated EFS at 36 months in research and control arms were 80% and 79% (log-rank p>0.9); OS were 90% and 87.2% (log-rank p=0.8) respectively. In patients with pCR, estimated EFS at 36 months was 90%, and with non-pCR was 70% (log-rank p < 0.001) and OS was 96% and 83% (log-rank p < 0.001) respectively. Neo-adjuvant olaparib did not improve pCR rates, EFS or OS when added to carboplatin/paclitaxel and anthracycline chemotherapy in patients with TNBC (gBRCAwt). This is in marked contrast to the major benefit of olaparib (gap schedule) in those with gBRCA pathogenic variants (gBRCAm) which is reported separately (gBRCAm article). ClinicalTrials.gov ID NCT03150576.

Environmental factors play a pivotal role in shaping the genetic and phenotypic diversity among organisms. Understanding the influence of the environment on a biological phenomenon is essential for deciphering the mechanisms resulting in trait differences among organisms. In this study, we present a novel approach utilizing an Artificial Neural Network (ANN) model to investigate the impact of environmental factors on a wide range of biological phenomena. Our proposed workflow includes hyperparameter optimization using model-based methods such as Bayesian and direct-search methods such as Random Search, and a new approach combining random search and linear models (RandomSearch+lm) to ensure a robust ANN architecture. Moreover, we employed a generalized version of the variable importance method to generate the feature importance metric using estimated weights from ANN. By applying this comprehensive ANN-based approach to functional genomics, we can gain valuable insights into the mechanisms underlying trait differentiation in organisms, while simultaneously enabling prediction and feature selection tasks. This methodology provides a robust and efficient framework for studying the complex relationships between environmental factors and biological features in biological systems.

Hydroxamic acids represent a group of weak organic acids, both naturally occurring and synthetically derived, characterized by the general formula RC(= O)N(R’OH). In this study, we investigated the binding behavior of N-m-tolyl-4-chlorophenoxyaceto hydroxamic acid with calf thymus DNA (ct-DNA) and torula yeast RNA (t-RNA) through a combination of techniques including UV–visible spectroscopy, fluorescence emission analysis, viscometry, and computational simulations using AutoDock4 software. Our findings reveal that the mode of binding between the compound and the nucleic acids is consistent with intercalation. Competitive binding experiments demonstrated that the complex competes effectively with ethidium bromide (EB) for binding to ct-DNA/t-RNA, displacing EB from its binding sites. Additionally, the introduction of the compound into the DNA-EB system resulted in a quenching of fluorescence emission peaks. Analysis of absorption spectra indicated a red shift and hypochromic shift when the compound interacted with DNA, further supporting the intercalative binding mode. The calculated binding constant (K b ) value for the compound is 6.62 × 10 4  M −1 and 5.40 × 10 3  M −1 indicating a strong interaction with ct-DNA and t-RNA respectively. We determined the Stern–Volmer constants for ct-DNA and t-RNA as 9.96 × 10 4  M −1 and 8.13 × 10 5  M −1 , respectively. The binding free energy values for ct-DNA/t-RNA were calculated to be − 3.741 × 10 7 and − 5.425 × 10 8  kcal/mol, respectively. Viscometric studies corroborated the UV results, showing a continuous increase in relative viscosity of ct-DNA/t-RNA solutions with the addition of the optimal hydroxamic acid concentration. Furthermore, we assessed the antioxidant activity of the compound using DPPH-radical scavenging and β-carotene linoleic acid assays. Gel electrophoresis results demonstrated the compound's remarkable efficacy in preventing DNA damage. Collectively, all experimental evidence supports the conclusion that N-m-tolyl-4-chlorophenoxyaceto hydroxamic acid binds to ct-DNA/t-RNA through an intercalative mechanism, which is consistent with our molecular docking simulations.

Due to advancements in technological trends, interest in frequency multipliers is increasing in the research community. However, the linearization approach on frequency multipliers differs from that of power amplifiers and hence cannot be directly implementable for end-to-end high-frequency systems. This paper discusses recent computational approaches and proposes a model for improving performance metrics, especially the adjacent channel power ratio. This paper shows theoretical trends, mathematical approaches to current trends, and the proposed model. It then establishes the theory by experimental implementation and compares the proposition results to the models in the literature.