Navigating Antibacterial Frontiers: A Panoramic Exploration of Antibacterial Landscapes, Resistance Mechanisms, and Emerging Therapeutic Strategies.

The development of effective antibacterial solutions has become paramount in maintaining global health in this era of increasing bacterial threats and rampant antibiotic resistance. Traditional antibiotics have played a significant role in combating bacterial infections throughout history. However, the emergence of novel resistant strains necessitates constant innovation in antibacterial research. We have analyzed the data on antibacterials from the CAS Content Collection, the largest human-curated collection of published scientific knowledge, which has proven valuable for quantitative analysis of global scientific knowledge. Our analysis focuses on mining the CAS Content Collection data for recent publications (since 2012). This article aims to explore the intricate landscape of antibacterial research while reviewing the advancement from traditional antibiotics to novel and emerging antibacterial strategies. By delving into the resistance mechanisms, this paper highlights the need to find alternate strategies to address the growing concern.

Long-term treatment with rilzabrutinib in patients with immune thrombocytopenia.

ABSTRACT: Immune thrombocytopenia (ITP) is an autoimmune disease associated with autoantibody-mediated platelet destruction and impaired platelet production, resulting in thrombocytopenia and a predisposition to bleeding. The ongoing, global phase 1/2 study showed that rilzabrutinib, a Bruton tyrosine kinase inhibitor specifically developed to treat autoimmune disorders, could be an efficacious and well-tolerated treatment for ITP. Clinical activity, durability of response, and safety were evaluated in 16 responding patients who continued rilzabrutinib 400 mg twice daily in the long-term extension (LTE) study. At LTE entry, the median platelet count was 87 × 109/L in all patients, 68 × 109/L in those who had rilzabrutinib monotherapy (n = 5), and 156 × 109/L in patients who received concomitant ITP medication (thrombopoietin-receptor agonists and/or corticosteroids, n = 11). At a median duration of treatment of 478 days (range, 303-764), 11 of 16 patients (69%) continued to receive rilzabrutinib. A platelet count of ≥50 × 109/L was reported in 93% of patients for more than half of their monthly visits. The median percentage of LTE weeks with platelet counts ≥30 × 109/L and ≥50 × 109/L was 100% and 88%, respectively. Five patients discontinued concomitant ITP therapy and maintained median platelet counts of 106 × 109/L at 3 to 6 months after stopping concomitant ITP therapy. Adverse events related to treatment were grade 1 or 2 and transient, with no bleeding, thrombotic, or serious adverse events. With continued rilzabrutinib treatment in the LTE, platelet responses were durable and stable over time with no new safety signals. This trial is registered at www.clinicaltrials.gov as #NCT03395210 and www.clinicaltrialsregister.eu as EudraCT 2017-004012-19.

Effect of a Standardized Ginger Root Powder Regimen on Chemotherapy-Induced Nausea and Vomiting: A Multicenter, Double-Blind, Placebo-Controlled Randomized Trial.

BACKGROUND: There is substantial interest in the role of ginger as an adjuvant therapy for chemotherapy-induced nausea and vomiting (CINV). However, available evidence lacks robust methodology. OBJECTIVE: To assess the effect of adjuvant ginger compared with placebo on chemotherapy-induced nausea-related quality of life (QoL) and CINV-related outcomes. DESIGN: A parallel, double-blind, placebo-controlled randomized trial with 1:1 allocation was conducted. PARTICIPANTS/SETTING: One hundred three chemotherapy-naïve adults scheduled to receive moderately to highly emetogenic chemotherapy at two hospitals in Australia were enrolled and analyzed. INTERVENTION: Four standardized ginger capsules (totaling 84 mg/day active gingerols/shogaols), or placebo, were administered commencing the day of chemotherapy and continuing for 5 days for chemotherapy cycles 1 through 3. MAIN OUTCOME MEASURES: The primary outcome was chemotherapy-induced nausea-related QoL. Secondary outcomes were vomiting- and CINV-related QoL; anticipatory, acute, and delayed nausea and vomiting; fatigue; nutritional status; depression and anxiety; health-related QoL; and adverse events. STATISTICAL ANALYSES PERFORMED: Intention-to-treat analysis was performed. Mixed analysis of variance with repeated measures determined differences between groups. The null hypothesis was no difference between groups. After applying a Bonferroni multiple testing correction, evidence against the null hypothesis was considered at P= 0.003. RESULTS: One hundred three participants (ginger: n = 52; placebo: n = 51) were enrolled and analyzed. There was clinically relevant evidence against the null hypothesis, favoring ginger, in change scores for nausea-related QoL (F[df] = 9.34[1,101]; P = 0.003; partial η2 = 0.09), overall CINV-related QoL (F[df] = 12.26[1,101]; P < 0.001; partial η2 = 0.11), delayed nausea severity (F[df] = 9.46[1,101]; P = 0.003; partial η2 = 0.09), and fatigue (F[df] = 10.11[1,101]; P = 0.002; partial η2 = 0.09). There was a clinically meaningful lower incidence of delayed nausea and vomiting in the ginger group at Cycle 2 (53% vs 75%; P = 0.020 and 4% vs 27%; P = 0.001, respectively) and Cycle 3 (49% vs 79%; P = 0.002 and 2% vs 23%; P = 0.001, respectively). There was a clinically meaningful lower incidence of malnutrition in the ginger group at Cycle 3 (18% vs. 41%; P = 0.032) and in change scores for Patient-Generated Subjective Global Assessment (F[df)] = 4.32[1,100]; P = 0.040; partial η2 = 0.04). Change scores between groups favored ginger for vomiting-related QoL and number of vomiting episodes; however, findings were not clinically meaningful. There was no effect of ginger on anticipatory or acute CINV, health-related QoL, anxiety, or depression. No serious adverse events were reported. CONCLUSIONS: Ginger supplementation was a safe adjuvant to antiemetic medications for CINV that enhanced QoL during chemotherapy treatment. Future trials are needed to examine dose-dependent responses to verify optimal dosing regimens.

The Evolving Landscape of Antibody-Drug Conjugates: In Depth Analysis of Recent Research Progress.

Antibody-drug conjugates (ADCs) are targeted immunoconjugate constructs that integrate the potency of cytotoxic drugs with the selectivity of monoclonal antibodies, minimizing damage to healthy cells and reducing systemic toxicity. Their design allows for higher doses of the cytotoxic drug to be administered, potentially increasing efficacy. They are currently among the most promising drug classes in oncology, with efforts to expand their application for nononcological indications and in combination therapies. Here we provide a detailed overview of the recent advances in ADC research and consider future directions and challenges in promoting this promising platform to widespread therapeutic use. We examine data from the CAS Content Collection, the largest human-curated collection of published scientific information, and analyze the publication landscape of recent research to reveal the exploration trends in published documents and to provide insights into the scientific advances in the area. We also discuss the evolution of the key concepts in the field, the major technologies, and their development pipelines with company research focuses, disease targets, development stages, and publication and investment trends. A comprehensive concept map has been created based on the documents in the CAS Content Collection. We hope that this report can serve as a useful resource for understanding the current state of knowledge in the field of ADCs and the remaining challenges to fulfill their potential.

The clinicopathological features of thrombosis with thrombocytopenia syndrome following ChAdOx1-S (AZD1222) vaccination and case outcomes in Australia: a population-based study.

Background: Thrombosis with thrombocytopenia syndrome (TTS) associated with viral vector COVID-19 vaccines, including ChAdOx1-S (AstraZeneca AZD1222) vaccine, can result in significant morbidity and mortality. We report the clinicopathological features of TTS following ChAdOx1-S vaccination and summarise the case outcomes in Australia. Methods: In this cohort study, patients diagnosed with TTS in Australia between 23 March and 31 December 2021 were identified according to predefined criteria. Cases were included if they met the Therapeutic Goods Administration (TGA) probable and confirmed case definitions and were reclassified using Centres for Disease Control and Prevention (CDC) definition for analysis. Data were collected on patient baseline characteristics, clinicopathological features, risk factors, treatment and outcomes. Findings: A total of 170 TTS cases were identified, with most occurring after the first dose (87%) of ChAdOx1-S. The median time to symptom onset after vaccination and symptom onset to admission was 11 and 2 days respectively. The median age of cases was 66 years (interquartile range 55-74). All except two patients received therapeutic anticoagulation and 66% received intravenous immunoglobulin. Overall, 85.3% of cases were discharged home after a median hospitalisation of 6 days, 9.4% required ongoing rehabilitation and 5.3% died. Eight deaths were related to TTS, with another dying from an unrelated condition while receiving treatment for TTS. Deaths occurred more commonly in those classified as Tier 1 according to the CDC definition and were associated with more severe thrombocytopenia and disease-related haemorrhage. Interpretation: TTS, while rare, can be severe and have catastrophic outcomes in some individuals. In Australia, the mortality rate was low compared to that reported in other high-income countries. Almost all received therapeutic anticoagulation with no bleeding complications and were successfully discharged. This emphasises the importance of community education and an established pathway for early recognition, diagnosis and treatment of TTS. Funding: Australian Commonwealth Department of Health and Aged Care. H.A Tran, N. Wood, J. Buttery, N.W. Crawford, S.D. Chunilal, V.M. Chen are supported by Medical Research Future Funds (MRFF) grant ID 2015305.

Formation of Ultracold Molecules by Merging Optical Tweezers.

We demonstrate the formation of a single RbCs molecule during the merging of two optical tweezers, one containing a single Rb atom and the other a single Cs atom. Both atoms are initially predominantly in the motional ground states of their respective tweezers. We confirm molecule formation and establish the state of the molecule formed by measuring its binding energy. We find that the probability of molecule formation can be controlled by tuning the confinement of the traps during the merging process, in good agreement with coupled-channel calculations. We show that the conversion efficiency from atoms to molecules using this technique is comparable to magnetoassociation.

Sustainable Fertilizers: Publication Landscape on Wastes as Nutrient Sources, Wastewater Treatment Processes for Nutrient Recovery, Biorefineries, and Green Ammonia Synthesis.

The ability of modern agriculture to meet future food demand imposed by accelerating growth of the world's population is a major challenge, and fertilizers play a key role by replacing nutrients in agricultural soil. Given the need for fertilizers, their cost in nonrenewable resources and energy, and the consequences of the greenhouse gas emissions required to make them, people have begun to explore ways to make fertilizer manufacturing and use more sustainable. Using data from the CAS Content Collection, this review examines and analyzes the academic and patent literature on sustainable fertilizers from 2001 to 2021. The breakdown of journal and patent literature publication over time on this topic, country or region of publications, the substances included in published research, among other things allow us to understand the general progress in the field as well as the classes of materials and concepts driving innovation. We hope that this bibliometric analysis and literary review will assist researchers in relevant industries to discover and implement ways to supplement conventional fertilizers and nutrient sources while improving the efficiency and sustainability of waste management and ammonia production.

Trends in Research and Development for CO2 Capture and Sequestration.

Technological and medical advances over the past few decades epitomize human capabilities. However, the increased life expectancies and concomitant land-use changes have significantly contributed to the release of ∼830 gigatons of CO2 into the atmosphere over the last three decades, an amount comparable to the prior two and a half centuries of CO2 emissions. The United Nations has adopted a pledge to achieve "net zero", i.e., yearly removing as much CO2 from the atmosphere as the amount emitted due to human activities, by the year 2050. Attaining this goal will require a concerted effort by scientists, policy makers, and industries all around the globe. The development of novel materials on industrial scales to selectively remove CO2 from mixtures of gases makes it possible to mitigate CO2 emissions using a multipronged approach. Broadly, the CO2 present in the atmosphere can be captured using materials and processes for biological, chemical, and geological technologies that can sequester CO2 while also reducing our dependence on fossil-fuel reserves. In this review, we used the curated literature available in the CAS Content Collection to present a systematic analysis of the various approaches taken by scientists and industrialists to restore carbon balance in the environment. Our analysis highlights the latest trends alongside the associated challenges.

Trends and Opportunities in Organic Synthesis: Global State of Research Metrics and Advances in Precision, Efficiency, and Green Chemistry.

Organic synthesis continues to drive a broad range of research advances in chemistry and related sciences. Another clear trend in organic synthesis research is the increasing desire to target improvements in the quality of life of humankind, new materials, and product specificity. Here, a landscape view of organic synthesis research is provided by analysis of the CAS Content Collection. Three emerging research directions, enzyme catalysis, photocatalysis, and green chemistry in organic synthesis, were identified and featured based on the publication trend analysis.

Trends and Opportunities in Organic Synthesis: Global State of Research Metrics and Advances in Precision, Efficiency, and Green Chemistry.

Organic synthesis continues to drive a broad range of research advances in chemistry and related sciences. Another clear trend in organic synthesis research is the increasing desire to target improvements in the quality of life of humankind, new materials, and product specificity. Here, a landscape view of organic synthesis research is provided by analysis of the CAS Content Collection. Three emerging research directions, enzyme catalysis, photocatalysis, and green chemistry in organic synthesis, were identified and featured based on the publication trend analysis.

Validating lactate dehydrogenase (LDH) as a component of the PLASMIC predictive tool (PLASMIC-LDH).

Background: The PLASMIC score is a convenient tool for predicting ADAMTS13 activity of <10%. Lactate dehydrogenase (LDH) is widely used as a marker of haemolysis in thrombotic thrombocytopenic purpura (TTP) monitoring, and could be used as a replacement marker for lysis. We aimed to validate the PLASMIC score in a multi-centre Asia Pacific region, and to explore whether LDH could be used as a replacement marker for lysis. Methods: Records of patients with thrombotic microangiopathy (TMA) were reviewed. Patients' ADAMTS13 activity levels were obtained, along with clinical/laboratory findings relevant to the PLASMIC score. Both PLASMIC scores and PLASMIC-LDH scores, in which LDH replaced traditional lysis markers, were calculated. We generated a receiver operator characteristics (ROC) curve and compared the area under the curve values (AUC) to determine the predictive ability of each score. Results: 46 patients fulfilled the inclusion criteria, of which 34 had ADAMTS13 activity levels of <10%. When the patients were divided into intermediate-to-high risk (scores 5‒7) and low risk (scores 0‒4), the PLASMIC score showed a sensitivity of 97.1% and specificity of 58.3%, with a positive predictive value (PPV) of 86.8% and negative predictive value (NPV) of 87.5%. The PLASMIC-LDH score had a sensitivity of 97.1% and specificity of 33.3%, with a PPV of 80.5% and NPV of 80.0%. Conclusion: Our study validated the utility of the PLASMIC score, and demonstrated PLASMIC-LDH as a reasonable alternative in the absence of traditional lysis markers, to help identify high-risk patients for treatment via plasma exchange.

Immune thrombocytopenia and COVID-19 vaccination: Outcomes and comparisons to prepandemic patients.

Background: Immune thrombocytopenia (ITP) has been reported following COVID-19 vaccination. After index case fatalities, there was concern among patients both with and without a prior history of ITP in Australia. Objectives: To describe treatment outcomes of ITP after COVID-19 vaccination and compare relapsed vs historical pre-COVID-19 ITP cohorts. Methods: We collected ITP cases in Australia within 6 weeks of receiving any COVID-19 vaccination as part of primary vaccination (up to October 17, 2021). Second, we reviewed platelet charts in a historical ITP cohort to determine whether platelet variability was distinct from relapsed ITP after vaccination. Results: We report on 50 patients (37 de novo, 13 relapsed ITP) vaccinated from March 22, 2021, to October 17, 2021. Although there was 1 fatality, bleeding was otherwise mostly minor: (70% WHO bleeding grade <2). De novo ITP was more likely after AstraZeneca ChAdOx1 nCoV-19 (89%) than Pfizer BNT162b2 (11%). Most patients responded quickly (median, 4 days; complete response, 40 of 45 [89%]). In the historical cohort, only 6 of 47 patients exhibited platelet variability (>50% decrease and platelets <100 × 109/L), but median platelet nadir was significantly higher than vaccination relapse (27 vs 6 × 109/L, P =.005). Conclusion: ITP was more frequently reported after AstraZeneca ChAdOx1 nCoV-19 than Pfizer BNT162b2 vaccination. Standard ITP treatments remain highly effective for de novo and relapsed ITP (96%). Although thrombocytopenia can be severe after vaccination, bleeding is usually mild. Despite some sampling bias, our data do not support a change in treatment strategies for patients with ITP after vaccination.

Acquired Hemophilia A Secondary to an Immune Checkpoint Inhibitor: A Case Report.

We report a case of a patient with extensive-stage SCLC who developed acquired hemophilia A during maintenance atezolizumab therapy. The patient initially presented with asymptomatic anemia, a prolonged acquired prothrombin time, and factor VIII (FVIII) deficiency. Acquired FVIII autoantibodies were detected, confirming the diagnosis of acquired hemophilia. Atezolizumab was ceased and high-dose prednisolone was initiated. He subsequently developed an extensive spontaneous upper limb subcutaneous hematoma and shoulder hemarthrosis despite improving FVIII inhibitor titers on prednisolone. His acute bleeding was successfully treated with recombinant factor VII, and rituximab was added to prednisolone. Given the quiescent malignancy, 16 months of preceding treatment with atezolizumab, and improvement with immunosuppression, a diagnosis of immune checkpoint inhibitor-induced hemophilia A was made. Severe hematologic immune-related adverse events such as this case of acquired hemophilia have rarely been reported in the literature.

Treatment of immune thrombocytopenia in Australian adults: A multicenter retrospective observational study.

Background: In Australia, prescribing restrictions limit access to internationally recommended second-line therapies such as rituximab and thrombopoietin agonists (TPO-A) (eltrombopag and romiplostim). Subsequent lines of therapy include an array of immunosuppressive and immune-modulating agents directed by drug availability and physician and patient preference. Objectives: The objective of the study was to describe the use of first and subsequent lines of treatment for adult immune thrombocytopenia (ITP) in Australia and to assess their effectiveness and tolerability. Patients/Methods: A retrospective review of medical records was conducted of 322 patients treated for ITP at eight participating centers in Australia between 2013 and 2020. Data were analyzed by descriptive statistics and frequency distribution using pivot tables, and comparisons between centers were assessed using paired t tests. Results: Mean age at diagnosis of ITP was 48.8 years (standard deviation [SD], 22.6) and 58.3% were women. Primary ITP was observed in 72% and secondary ITP in 28% of the patients; 95% of patients received first-line treatment with prednisolone (76%), dexamethasone (15%), or intravenous immunoglobulin (48%) alone or in combination. Individuals with secondary ITP were less steroid dependent (72% vs. 76%) and required less treatment with a second-line agent (47% vs. 58%) in the study sample. Over half (56%) of the cohort received treatment with one or more second-line agents. The mean number of second-line agents used for each patient was 1.9 (SD, 1.2). The most used second-line therapy was rituximab, followed by etrombopag and splenectomy. These also generated the highest rates of complete response (60.3%, 72.1%, and 71.8% respectively). The most unfavorable side effect profiles were seen in long-term corticosteroids and splenectomy. Conclusion: A wide range of "second-line" agents were used across centers with variable response rates and side effect profiles. Findings suggest greater effectiveness of rituximab and TPO-A, supporting their use earlier in the treatment course of patients with ITP across Australia.

Assessment of immunological anti-platelet factor 4 antibodies for vaccine-induced thrombotic thrombocytopenia (VITT) in a large Australian cohort: A multicenter study comprising 1284 patients.

BACKGROUND: Vaccine-induced thrombotic thrombocytopenia (VITT) is a rare complication of adenovirus-based vaccines aimed to prevent and minimize COVID-19 and related pathophysiology. OBJECTIVES: To describe patterns of testing for anti-platelet factor 4 (PF4) antibodies using various ELISA assays in a large Australian cohort and comparative functional platelet activation assays in a subset. PATIENTS/METHODS: Asserachrom HPIA IgG ELISA was performed in 1284 patients over a period of 12 months, supplemented in select cohorts by comparative ELISA using three other methods (n = 78-179), three different functional assays (flow cytometry, serotonin release assay, and/or Multiplate; n = 476), and rapid immunological chemiluminescence anti-PF4 assay (n = 460), in a multicenter study. RESULTS: For first episode presentations, 190/1284 (14.8%) ELISA tests were positive. Conversely, most (445/460; 96.7%) chemiluminescence anti-PF4 test results were negative. All functional assays showed associations of higher median ELISA optical density with functional positivity and with high rates of ELISA positivity (64.0% to 85.2%). Data also identified functional positivity in 14.8%-36.0% of ELISA negative samples, suggesting false negative VITT by HPIA IgG ELISA in upward of one third of assessable cases. CONCLUSION: To our knowledge, this is the largest multicenter evaluation of anti-PF4 testing for investigation of VITT. Discrepancies in test results (ELISA vs. ELISA or ELISA vs. functional assay) in some patients highlighted limitations in relying on single methods (ELISA and functional) for PF4 antibody detection in VITT, and also highlights the variability in phenotypic test presentation and pathomechanism of VITT.

Rilzabrutinib, an Oral BTK Inhibitor, in Immune Thrombocytopenia.

BACKGROUND: Rilzabrutinib, an oral, reversible covalent inhibitor of Bruton's tyrosine kinase, may increase platelet counts in patients with immune thrombocytopenia by means of dual mechanisms of action: decreased macrophage (Fcγ receptor)-mediated platelet destruction and reduced production of pathogenic autoantibodies. METHODS: In an international, adaptive, open-label, dose-finding, phase 1-2 clinical trial, we evaluated rilzabrutinib therapy in previously treated patients with immune thrombocytopenia. We used intrapatient dose escalation of oral rilzabrutinib over a period of 24 weeks; the lowest starting dose was 200 mg once daily, with higher starting doses of 400 mg once daily, 300 mg twice daily, and 400 mg twice daily. The primary end points were safety and platelet response (defined as at least two consecutive platelet counts of ≥50×103 per cubic millimeter and an increase from baseline of ≥20×103 per cubic millimeter without the use of rescue medication). RESULTS: Sixty patients were enrolled. At baseline, the median platelet count was 15×103 per cubic millimeter, the median duration of disease was 6.3 years, and patients had received a median of four different immune thrombocytopenia therapies previously. All the treatment-related adverse events were of grade 1 or 2 and transient. There were no treatment-related bleeding or thrombotic events of grade 2 or higher. At a median of 167.5 days (range, 4 to 293) of treatment, 24 of 60 patients (40%) overall and 18 of the 45 patients (40%) who had started rilzabrutinib treatment at the highest dose met the primary end point of platelet response. The median time to the first platelet count of at least 50×103 per cubic millimeter was 11.5 days. Among patients with a primary platelet response, the mean percentage of weeks with a platelet count of at least 50×103 per cubic millimeter was 65%. CONCLUSIONS: Rilzabrutinib was active and associated with only low-level toxic effects at all dose levels. The dose of 400 mg twice daily was identified as the dose for further testing. Overall, rilzabrutinib showed a rapid and durable clinical activity that improved with length of treatment. (Funded by Sanofi; ClinicalTrials.gov number, NCT03395210; EudraCT number, 2017-004012-19.).

Multiterritorial strokes in the setting of spontaneous heparin-induced thrombocytopaenia syndrome.

We present a case study of a 38-year-old man who developed arterial and venous thrombi, resulting in multiterritorial strokes, a pulmonary embolus and a cerebral venous sinus thrombosis in the setting of spontaneous heparin-induced thrombocytopaenia syndrome.

Consensus guidelines for the management of adult immune thrombocytopenia in Australia and New Zealand.

INTRODUCTION: The absence of high quality evidence for basic clinical dilemmas in immune thrombocytopenic purpura (ITP) underlines the need for contemporary guidelines relevant to the local treatment context. ITP is diagnosed by exclusions, with a hallmark laboratory finding of isolated thrombocytopenia. MAIN RECOMMENDATIONS: Bleeding, family and medication histories and a review of historical investigations are required to gauge the bleeding risk and possible hereditary syndromes. Beyond the platelet count, the decision to treat is affected by individual bleeding risk, disease stage, side effects of treatment, concomitant medications, and patient preference. Treatment is aimed at achieving a platelet count > 20 × 109 /L, and avoidance of severe bleeding. Steroids are the standard first line treatment, with either 6-week courses of tapering prednisone or repeated courses of high dose dexamethasone providing equivalent efficacy. Intravenous immunoglobulin can be used periprocedurally or as first line therapy in combination with steroids. CHANGES IN MANAGEMENT AS A RESULT OF THIS STATEMENT: There is no consensus on choice of second line treatments. Options with the most robust evidence include splenectomy, rituximab and thrombopoietin receptor agonists. Other therapies include azathioprine, mycophenolate mofetil, dapsone and vinca alkaloids. Given that up to one-third of patients achieve a satisfactory haemostatic response, splenectomy should be delayed for at least 12 months if possible. In life-threatening bleeding, we recommend platelet transfusions to achieve haemostasis, along with intravenous immunoglobulin and high dose steroids.