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Chris Kiff,1 Sandrine Ruiz,2 Nebibe Varol,3 Danny Gibson,4 Andrew Davies,1 Debasree Purkayastha5 1ICON plc, Abingdon, UK; 2AstraZeneca, Barcelona, Spain; 3AstraZeneca, Cambridge, UK; 4AstraZeneca, Luton, UK; 5Phastar, Manchester, UK Purpose: Patients with severe COPD are at high risk of experiencing disease exacerbations, which require additional treatment and are associated with elevated mortality and increased risk of future exacerbations. Some patients continue to experience exacerbations despite receiving triple inhaled therapy (ICS plus LAMA plus LABA). Roflumilast is recommended by the Global Initiative for Chronic Obstructive Lung Disease as add-on treatment to triple inhaled therapy for these patients. This cost-effectiveness analysis compared costs and quality-adjusted life-years for roflumilast plus triple inhaled therapy vs triple inhaled therapy alone, using data from the REACT and RE2SPOND trials. Patients and methods: Patients included in the analysis had severe to very severe COPD, FEV1

An exceedingly porous and interwoven fibrous structure was achieved in this study by interlocking titanium carbide (Ti 3 C 2 ) MXenes onto the electrospun mats using poly(vinylidene fluoride) (PVDF) as the base polymer. The fibrous membrane was further modified with the inclusion of zinc oxide (ZnO) and tungstite (WO 3 ·H 2 O) nano/microstructures via annealing and hydrothermal approaches. Through these strategic interfaced morphological developments in novel Ti 3 C 2 /ZnO/WO 3 ·H 2 O heterostructures, our findings reveal enhanced wettability and charge-segregation desirable for promoting oil-water separation and photoreactivity, respectively. The superhydrophilic hierarchical architectures offer optimal separation potential for stable oil-water emulsions with a higher flux. Additionally, when exposed to LED light, the composite membrane demonstrated an enhanced photocatalytic capacity for the removal of organic contaminants. This simple, inexpensive, and eco-friendly approach may thus promote the route for the fabrication of 2D MXene-based multifunctional membranes for effective treatment of complex oily wastewater.

Competing Interests: Declaration of interests The authors declare no competing interests.

This paper intends to position the key theoretical understanding of universal design from a global lens to the contemporary times, especially with insights from India as a majority world perspective. Using a narrative-based approach, it combines theoretical insights with experiential insights through state-of-the-art literature and understanding. A seven-lens framework is proposed as a comprehensive approach towards UD viz. the human diversity and demographic lens, the socio-cultural lens, the environment and ecology lens, the economic lens, the technology lens, the policy lens and the philosophy lens. Each lens shares unique perspectives with Universal Design as a shared concept for application evolving a discourse for a human-centric and sustainable futures. It highlights various paradigms originating from the Indian context representing high population perspectives especially the context of economic inclusion through universal design with affordability as a key value. The discussion leads us into understanding contextual relevance of UD beyond its original intent of universal accessibility itself. It concludes to see and propose UD as an integral layer of sustainability with a common goal of sustenance and inclusion.

Public toilets fulfil an essential need for all human beings. In the context of India, the diversity of population implies a diverse set of complex barriers in the public toilet experience. Inclusion and the contextual translation of universal design becomes crucial, considering the distinct socio-cultural dimensions. This study intends to enquire the above-mentioned perspective and contribute towards an understanding of inclusion and universal design in public toilets. The methodology is a three-part process including literature review, experiential case reflections and ethnographic field perspectives. The gathered data is mapped thematically and assessed qualitatively, based on the existing principles of universal design. The insights from the assessment highlight the need for contextualization of existing universal design principles, bringing out a multi-dimensional complexity of inclusion across human needs, behaviour, physical, planning and service aspects. This study paves a way forward for evolving design directions by raising further questions through fresh perspectives on inclusion & accessibility in public toilets. The raised questions contribute to a dilemma of standardisation versus contextual customisation around the understanding of inclusion and universal design, focusing on the scenario of Indian public toilets.

Over the last decade, commercialization of insects for food and feed has been exponentially increasing. Insect protein is emerging as a sustainable livestock feed and human food alternative due to its low land and carbon footprint. The principles of insect industry are deeply embedded in the core values of sustainability and circular economy. Black soldier fly (BSF) is the crown jewel of insect industry and is one of the most commercially farmed insects. However, this steadfast growth is accompanied by generation of insect based biowaste such as dead flies and pupae exuviae. This will be a major waste fraction from this industry. This study discusses the valorization potential of this waste into chitin (which finds application in cosmetics, bioplastics, and pesticides, among other industries), biogas, fertilizer, and biochar. There is need to conduct more explorative research on value proposition of insect based biowaste to ensure that this industry can comply fully with circular economy and sustainability principles., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Debasree Purkayastha reports financial support was provided by European Commission. Debasree Purkayastha reports a relationship with Nord University - Steinkjer that includes: employment and funding grants. Prabhat Khanal reports a relationship with Nord University - Steinkjer that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In addressing the pressing environmental challenges posed by frequent oil spills, this work presents a novel approach of synthesizing a superhydrophobic three-dimensional (3D) porous melamine sponge (MS). CuO and ZnO nanoparticles were grown on the MS via a hydrothermal method to create MS/CuO/ZnO with multiscale hierarchical nanostructures. The resulting material exhibited a stable water contact angle of 155° through various tests. MS/CuO/ZnO demonstrated exceptional oil absorption capacities (40-145 g/g and 0.83-0.99 mL.cm -3 ), surpassing 98% efficiency in oil separation, and retained reusability for 10 cycles. Impressively, the sponge achieved successful separation of oil/water emulsions with a permeation flux of 14870 L m -2 h -1 . The composite sponge, distinguished by its high photodegradation ability, can degrade both water- and oil-targeted pollutants under visible light irradiation from light-emitting diode (LED). With its remarkable attributes including superior oil absorption, excellent oil/water separation, mechanical resistance, and excellent photocatalytic ability, it exhibits considerable potential for applications in both wastewater treatment and large-scale marine oil spill response. The easily prepared MS/CuO/ZnO emerges as a versatile solution capable of addressing pressing challenges and marking a significant leap toward sustainable and impactful environmental remediation.

MXene, a recently emerged 2D material, has garnered substantial attention for a myriad of applications. Despite the growing interest, there remains a noticeable gap in exploring MXene-based membranes for the simultaneous achievement of photomodulated oil/water separation, bacterial resistance, and the removal of pollutants in the treatment of oily wastewater. In this work, we have successfully synthesized a novel multifunctional CuO@MXene-PAN nanofibrous membrane (NFM) featuring unique nanograin-like structures. Benefitting from these unique structures, the resultant membrane shows excellent superwetting properties, significantly enhancing its performance in oil/water separation. In addition, the membrane's photothermal property boosts its permeance by 40% under visible light illumination within 30 min. Furthermore, the resultant membrane shows decent dye removal efficiency in an aqueous solution, e.g., Rhodamine B (RhB), promoting efficient degradation with high reusability under visible light. Most remarkably, the resultant membrane exhibits superior anti-biofouling capability and consistently resists the adhesion of microorganisms such as cyanobacteria over a 14 day period. Thus, the combined effect of superior superwetting properties, photothermal responsivity, photocatalytic activity, and the antibacterial effect in CuO@MXene-PAN NFM contributes to the efficient treatment of intricate oily wastewater. This synergistic combination of superior properties in the membrane could be an appealing strategy for the broad development of multifunctional materials to prevent fouling during actual separation performance.

Purpose: Exacerbations of chronic obstructive pulmonary disease (COPD) are associated with deteriorating health and health-related quality of life (HRQoL) among people with COPD during and after events. HRQoL data are key to evaluating treatment cost-effectiveness and informing reimbursement decisions in COPD. EuroQoL 5-dimension 5-level (EQ-5D-5L) utility scores, based on various HRQoL measures, are used in economic evaluations of pharmacotherapy. These analyses estimated associations between EQ-5D-5L utility scores and exacerbations (new and previous) in patients with moderate-to-very severe COPD., Methods: Longitudinal mixed models for repeated measures (MMRM), adjusted for time and treatment, were conducted using data from the ETHOS study (NCT02465567); models regressed EQ-5D-5L on current and past exacerbations that occurred during the study, adjusting for other patient reported outcomes and clinical factors., Results: Based on the simplest covariate adjusted model (adjusted for current exacerbations and number of previous exacerbations during the study), a current moderate exacerbation was associated with an EQ-5D-5L disutility of 0.055 (95% confidence interval: 0.048, 0.062) with an additional disutility of 0.035 (0.014, 0.055) if the exacerbation was severe. After resolving, each prior exacerbation was associated with a disutility that persisted for the remainder of the study (moderate exacerbation, 0.014 [0.011, 0.016]; further disutility for severe exacerbation, 0.011 [0.003, 0.018])., Conclusion: An EQ-5D-5L disutility of 0.090 was associated with a current severe exacerbation in ETHOS. Our findings suggest incorporating the effects of current, recently resolved, and cumulative exacerbations into economic models when estimating benefits and costs of COPD pharmacotherapy, as exacerbations have both acute and persistent effects., (© 2024. The Author(s).)

The C-terminal domain (CTD) of RNA polymerase II plays a crucial role in regulating transcription dynamics in eukaryotes. The phosphorylation of serine residues within the CTD controls transcription initiation, elongation, and termination. While the CTD is highly conserved across eukaryotes, lower eukaryotes like protists, including Plasmodium, exhibit some differences. In this study, we performed a comparative analysis of CTD in eukaryotic systems to understand why the parasites evolved in this particular manner. The Plasmodium falciparum RPB1 is exceptionally large and feature a gap between the first and second heptad repeats, resulting in fifteen canonical heptad repeats excluding the initial repeat. Analysis of this intervening sequence revealed sub motifs of heptads where two serine residues occupy the first and fourth positions (S 1 X 2 X 3 S 4 ). These motifs lie in the intrinsically disordered region of RPB1, a characteristic feature of the CTD. Interestingly, the S 1 X 2 X 3 S 4 sub-motif was also observed in early-divergingeukaryotes like Leishmania major, which lack canonical heptad repeats. Furthermore, eukaryotes across the phylogenetic tree revealed a sigmoid pattern of increasing serine frequency in the CTD, indicating that serine enrichment is a significant step in the evolution of heptad-rich RPB1. Based on these observations and analysis, we proposed an evolutionary model for RNA Polymerase II CTD, encompassing organisms previously deemed exceptions, notably Plasmodium species. Thus, our study provides novel insights into the evolution of the CTD and will prompt further investigations into the differences exhibited by Plasmodium RNA Pol II and determine if they confer a survival advantage to the parasite., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Prolonged intermittent renal replacement therapy (PIRRT) is gaining popularity as a renal replacement modality in intensive care units, but there is a relative lack of guidance regarding antimicrobial clearance and dosing when compared with other modalities. The objectives of this systematic review were to: (1) identify and describe the pharmacokinetics (PK) of relevant antimicrobials used in critically ill adults receiving PIRRT, (2) evaluate the quality of evidence supporting these data, and (3) propose dosing recommendations based on the synthesis of these data. A search strategy for multiple databases was designed and executed to identify relevant published evidence describing the PK of antimicrobials used in critically ill adults receiving PIRRT. Quality assessment, evaluation of reporting, and relevant data extraction were conducted in duplicate. Synthesis of PK/pharmacodynamic (PD) outcomes, dosing recommendations from study authors, and physicochemical properties of included antibiotics were assessed by investigators in addition to the quality of evidence to develop dosing recommendations. Thirty-nine studies enrolling 452 patients met criteria for inclusion and provided PK and/or PD data for 20 antimicrobials in critically ill adults receiving PIRRT. Nineteen studies describe both PK and PD outcomes. Vancomycin (12 studies, 171 patients), meropenem (7 studies, 84 patients), and piperacillin/tazobactam (5 studies, 56 patients) were the most frequent antimicrobials encountered. The quality of evidence was deemed strong for 7/20 antimicrobials, and strong dosing recommendations were determined for 9/20 antimicrobials. This systematic review updates and addresses issues of quality in previous systematic reviews on this topic. Despite an overall low quality of evidence, strong recommendations were able to be made for almost half of the identified antimicrobials. Knowledge gaps persist for many antimicrobials, and higher quality studies (i.e., population PK studies with assessment of PD target attainment) are needed to address these gaps., (© 2023 Pharmacotherapy Publications, Inc.)

Tyrosine kinase inhibitor therapy revolutionized chronic myeloid leukemia treatment and showed how targeted therapy and molecular monitoring could be used to substantially improve survival outcomes. We used chronic myeloid leukemia as a model to understand a critical question: why do some patients have an excellent response to therapy, while others have a poor response? We studied gene expression in whole blood samples from 112 patients from a large phase III randomized trial (clinicaltrials gov. Identifier: NCT00471497), dichotomizing cases into good responders (BCR::ABL1 ≤10% on the International Scale by 3 and 6 months and ≤0.1% by 12 months) and poor responders (failure to meet these criteria). Predictive models based on gene expression demonstrated the best performance (area under the curve =0.76, standard deviation =0.07). All of the top 20 pathways overexpressed in good responders involved immune regulation, a finding validated in an independent data set. This study emphasizes the importance of pretreatment adaptive immune response in treatment efficacy and suggests biological pathways that can be targeted to improve response.

The combination of CFTR modulators ivacaftor, tezacaftor and elexacaftor (Trikafta®, Kaftrio®) significantly improve outcomes, including survival in a broad range of cystic fibrosis patients. These drugs have complicated metabolic profiles that make the potential for drug interactions an important consideration for prescribers, care providers and patients. Prolonged survival also increases risk of age-related disease and their associated pharmacotherapy, further increasing the risk of drug interactions and the need for increased vigilance amongst care providers. We systematically searched the literature for studies identifying and evaluating pharmacokinetic and pharmacodynamic drug interactions involving the components of Trikafta®/Kaftrio®. We also searched electronic databases of drugs for possible drug interactions based on metabolic profiles. We identified 86 potential drug interactions of which 13 were supported by 14 studies. There is a significant need for research to describe the likelihood, magnitude and clinical impact of the drug interactions proposed here., Competing Interests: Declaration of Competing Interest All authors have no conflicts of interest or competing interests to declare., (Copyright © 2023. Published by Elsevier B.V.)

In this study, Black Soldier Fly Larvae (BSFL)-based technology has been proposed and tested for treatment and valorization of human faeces, food waste and a mixture of 75% human faeces with 25% food waste. Experiments were conducted between 15 and 45 °C and 55-75% relative humidity. BSFL's performance for the degradation of the mixed waste was significantly better than their performances when used for the degradation of either human faeces or food waste fed alone, primarily due to the availability of more conducive pH, and better microbial and nutrient balance. The abiotic factors, temperature and relative humidity impacted the decomposition rate and weight gain pattern of BSFL when they were fed on the waste streams. The results showed that the optimum conditions to conduct the proposed BSFL-based treatment was 31-35 °C and 55-75% RH. The protein content in the BSFL was not impacted significantly by the quality of the waste stream, whereas the fat content varied substantially. The abiotic factors also impacted the protein and fat content of BSFL. The investigation led to the estimation of the decomposition rates over a wide range of temperature and relative humidity conditions, which could be useful for the design of large-scale BSFL-based treatment plants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Access to water, sanitation, and hygiene (WASH) for all is fundamental for sustenance. Goal 6 of the UN's Sustainable Development Goals urges that 'universal access to drinking water, sanitation and hygiene' is fundamental as a response in the current post-COVID scenario. Despite Government of India's efforts through programs like Swachh Bharat (Clean India) Mission, there is a long way to go to integrate equity and inclusion in the sanitation facilities of the public realm. This paper is an attempt to understand the aspect of inclusion in sanitation systems of urban public spaces of India, limiting the study to Delhi and Noida, which are in the National Capital Region (NCR). The aim is to explore the contextual challenges of universal design in public sanitation and develop an understanding of what makes a public toilet inclusive in the urban Indian context. A field-based, mixed methods approach is followed which begins with a literature review of government policies & schemes and theoretical understanding of inclusion as well as the role of universal design as an approach to achieve inclusion. This is followed by on-ground studies involving ethnographic surveys, analysis of imagery and field observations. The results show an analysis of the inclusive aspects of sanitation under the thematic domains of public perception, usage preferences and issues in the public toilet experience. The sanitation facilities in urban public spaces are used by a diverse population and the results showcase a collection of the qualitative experiences of a varied set of user groups. The subjective challenges of inclusive sanitation are highlighted through the various stages and components of the entire sanitation system - the design & infrastructure, operations & maintenance, and behavioural patterns. This paper tries to raise new grounded questions to further explore the highlighted marginal distinctions between inclusion and accessibility in the urban public sanitation experience of India.

Background: Recognition and management of adverse events (AEs) associated with immune checkpoint inhibitor (ICI) use by cancer patients requires expertise from multiple disciplines. Greater awareness of potential AEs may result in earlier recognition, appropriate management, and better patient outcomes., Objective: The primary objective of this overview of systematic reviews was to synthesize and consolidate systematic review evidence describing the incidence proportion and severity of AEs associated with various ICI therapies across different cancers., Methods: A systematic literature search of four databases was conducted to identify systematic reviews that describe the incidence proportion and severity of AEs related to ICI therapy in cancer patients. A systematic review was eligible if it included adults with cancer; on ICI alone or in combination with another ICI, chemotherapy, or targeted therapy; severity (graded according to the Common Terminology Criteria for Adverse Events) and incidence proportion of AEs and whether it reported its eligibility criteria. AEs of interest were identified through an iterative ranking exercise by key stakeholders and knowledge users. Extraction of PICOTTS elements and quality indicators (AMSTAR-2) were used to manage overlap of primary studies across systematic reviews at the outcome level. Cancer subtypes were mapped to drug class and AE severity., Results: Overall, 129 systematic reviews met the inclusion criteria for data mapping. Systematic reviews reported incidence proportions for more than 76 AEs, of which 34 were identified as AEs of interest. After overlap assessment, 65 systematic reviews were chosen for data extraction. The three AEs with the highest median incidence were fatigue (18.3%, interquartile range [IQR] 15.0-28.0%), diarrhea (15.3%, IQR 9.7-29.2%) and rash (14.4%, IQR 10.3-19.2%). The three AEs (high-grade) with the highest median incidence were diarrhea (1.5%, IQR 1.2-6.0%), colitis (1.3%, IQR 0.6-6.1%) and neutropenia (1.2%, IQR 0.4-3.3%). Incidence proportions of high-grade AEs were often considerably lower than all-grade AEs and combination therapy (ICI combinations or combinations of ICI with chemotherapy or targeted therapy) was responsible for some of the highest incidence proportions regardless of AE. Rare AEs and certain cancer subtypes were not well reported., Conclusions: Early recognition of AEs associated with ICIs requires expertise from diverse specialists, not just oncologists. Greater awareness of potential AEs may result in earlier recognition, appropriate management, and better patient outcomes., Prospero Registration: CRD42021231593., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The commingled nature of the municipal solid waste in many developing nations is one of the primary reasons behind the failure to its successful management. Although there are technologies to effectively treat and process well-segregated and classified waste, they are ineffective in managing the commingled waste. Commingled waste has neither calorific value enough to support waste-to-energy operations nor is it suitable for producing quality compost to generate market value. In this article, a novel Black Soldier Fly Larva (BSFL) -based technology has been proposed and tested to auto-segregate and treat the biodegradable fraction of the Commingled Municipal Solid Waste (CMSW). Several BSFL feeding experiments on five different CMSW compositions were conducted at various temperatures and relative humidity conditions. BSFL could selectively consume the biodegradable fraction of the CMSW to convert it into its body mass and separate itself from the rest of the waste, which mainly consisted of inert and recyclable waste fractions that can be further treated using appropriate waste treatment technology. The mature larvae or the pre-pupae grown at the expense of the biodegradable waste fraction can find several commercial uses. The larvae's consumption rate and weight gain were dependent on the environmental conditions; 30 °C and relative humidity of 65-75% provided the highest consumption rate and most significant weight gain. The batch experiments in the laboratory proved that BSFL could be promising for the treatment of CMSW. The experimental data presented may help design a process for further scaling up an effective treatment method for CMSW, which might benefit many developing nations in managing their waste effectively and economically., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: Standard-of-care treatment for metastatic hormone receptor-positive (HR + ), HER2-negative (HER2 - ) breast cancer includes endocrine therapy (ET) combined with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i). Optimal treatment after progression on CDK4/6i is unknown. The TRINITI-1 trial investigated ribociclib, a CDK4/6i that has recently demonstrated significant overall survival benefit in two phase III trials, in combination with everolimus and exemestane in patients with HR + , HER2 - advanced breast cancer (ABC) after progression on a CDK4/6i., Patients and Methods: This multicenter, open-label, single-arm, phase I/II study included patients with locally advanced/metastatic HR + /HER2 - breast cancer. The primary endpoint was clinical benefit rate (CBR) at week 24 among patients with ET-refractory disease with progression on a CDK4/6i. Other endpoints included safety and biomarker analysis., Results: Of 104 patients enrolled (phases I and II), 96 had prior CDK4/6i. Recommended phase II doses (all once daily days 1-28 of 28-day cycle) were ribociclib 300 mg, everolimus 2.5 mg, and exemestane 25 mg (group 1) and ribociclib 200 mg, everolimus 5 mg, and exemestane 25 mg (group 2). CBR among 95 efficacy-evaluable patients (phases I and II) at week 24 was 41.1% (95% confidence interval, 31.1-51.6), which met the primary endpoint (predetermined threshold: 10%). Common adverse events included neutropenia (69.2%) and stomatitis (40.4%). No new safety signals were observed; no grade 3/4 QTc prolongation was reported., Conclusions: Preliminary TRINITI-1 safety and efficacy results support further investigation of CDK4/6 blockade and targeting of the PI3K/AKT/mTOR signaling pathway in patients with ET-refractory HR + /HER2 - ABC after progression on a CDK4/6i., (©2021 American Association for Cancer Research.)

We evaluated standard-of-care (SOC) treatment with or without midostaurin to prevent relapse following allogeneic hematopoietic stem cell transplant (alloHSCT) in patients with acute myeloid leukemia (AML) harboring internal tandem duplication (ITD) in FLT3. Adults (aged 18-70 years) who received alloHSCT in first complete remission, had achieved hematologic recovery, and were transfusion independent were randomized to receive SOC with or without midostaurin (50 mg twice daily) continuously in twelve 4-week cycles. The primary endpoint was relapse-free survival (RFS) 18 months post-alloHSCT. Sixty patients were randomized (30/arm); 30 completed all 12 cycles (midostaurin + SOC, n = 16; SOC, n = 14). The estimated 18-month RFS (95% CI) was 89% (69-96%) in the midostaurin arm and 76% (54-88%) in the SOC arm (hazard ratio, 0.46 [95% CI, 0.12-1.86]; P = 0.27); estimated relapse rates were 11% and 24%, respectively. Inhibition of FLT3 phosphorylation to <70% of baseline (achieved by 50% of midostaurin-treated patients) was associated with improved RFS. The most common serious adverse events were diarrhea, nausea, and vomiting. Rates of graft-vs-host disease were similar between both arms (midostaurin + SOC, 70%; SOC, 73%). The addition of midostaurin maintenance therapy following alloHSCT may provide clinical benefit in some patients with FLT3-ITD AML. (ClinicalTrials.gov identifier: NCT01883362).

Autism Spectrum Disorder (ASD) is a neurological disorder which might have a lifelong impact on the language learning, speech, cognitive, and social skills of an individual. Its symptoms usually show up in the developmental stages, i.e., within the first two years after birth, and it impacts around 1% of the population globally [https://www.autism-society.org/whatis/facts-and-statistics/. Accessed 25 Dec 2019]. ASD is mainly caused by genetics or by environmental factors; however, its conditions can be improved by detecting and treating it at earlier stages. In the current times, clinical standardized tests are the only methods which are being used, to diagnose ASD. This not only requires prolonged diagnostic time but also faces a steep increase in medical costs. To improve the precision and time required for diagnosis, machine learning techniques are being used to complement the conventional methods. We have applied models such as Support Vector Machines (SVM), Random Forest Classifier (RFC), Naïve Bayes (NB), Logistic Regression (LR), and KNN to our dataset and constructed predictive models based on the outcome. The main objective of our paper is to thus determine if the child is susceptible to ASD in its nascent stages, which would help streamline the diagnosis process. Based on our results, Logistic Regression gives the highest accuracy for our selected dataset., Competing Interests: Conflict of interestOn behalf of all authors, the corresponding author states that there is no conflict of interest., (© The Author(s), under exclusive licence to Springer Nature Singapore Pte Ltd 2021.)

Approval of midostaurin, a multikinase inhibitor, in combination with chemotherapy for the treatment of adults with newly diagnosed FLT3 mutation-positive acute myeloid leukemia, was based on the phase 3 RATIFY trial results. RADIUS-X (NCT02624570) was an expanded access program providing access to midostaurin during regulatory review and extending the understanding of the safety and tolerability of midostaurin. Patients aged ≥18 years received midostaurin with 1-2 cycles of induction therapy (cytarabine plus daunorubicin or idarubicin) and ≤4 cycles of high-dose cytarabine consolidation chemotherapy or as single-agent maintenance therapy. The study enrolled 103 patients. No new safety events were observed; toxicities were not influenced by age, anthracycline choice, or coadministration of CYP3A4 inhibitors. The most common adverse events (AEs) were febrile neutropenia, nausea, and diarrhea. During maintenance, 46% of patients reported AEs. Midostaurin demonstrated a manageable safety profile and was associated with high transplant and low on-treatment relapse rates.

Purpose: As part of the Novartis Signature Program, this study evaluated the efficacy of ribociclib (selective cyclin-dependent kinase 4/6 [CDK4/6] inhibitor) in patients with cyclin D-CDK4/6 pathway-aberrant tumors., Methods: This was a phase II, single-arm, signal-seeking study in patients with advanced malignancies that had progressed on or after standard treatment. Prior identification of tumor CDK4/6 mutation or amplification, CCND1 /3 amplification, or CDKN2A mutation or loss was required. Clinical benefit (defined as the proportion of patients with response or stable disease at ≥ 16 weeks) was the primary end point., Results: From 61 centers in the United States, 106 patients (median age, 62.5 years) were enrolled across multiple malignancies. The patient population was heavily pretreated (median number of prior therapies, three; range, 0 to 19). Median progression-free survival was 1.8 months (95% CI, 1.8 to 1.9). In patients with solid tumors, the clinical benefit rate was 18.1% (n = 19 of 105) and the overall response rate was 2.9% (n = 3 of 105); three partial responses occurred in patients with adenocarcinoma (unknown primary), soft tissue sarcoma, and urothelial carcinoma. No tumor cohort met the prespecified criteria for success. The most common adverse events suspected to be related to treatment were neutropenia (30.2%; decreased neutrophils, 15.1%), fatigue (31.1%), and nausea (29.2%). Fatigue and nausea were typically mild. Only one incident of febrile neutropenia was experienced (grade 3)., Conclusion: No new or unexpected safety signals were observed in this heavily pretreated patient population. Although responses were seen in tumors with CCND1 - CDK4/6 amplifications, the primary end point was not met, suggesting additional evaluation of ribociclib, possibly as combination therapy, is needed.

Background: Phosphatidylinositol 3-kinase (PI3K) pathway activation plays a key role in tumorigenesis and has been associated with poor prognosis and resistance to multiple therapies in various cancers. Results: There were 146 patients enrolled; common tumor types were colorectal, sarcoma, and ovarian. Tumors had PI3K pathway alterations and a median of four mutations with tissue-specific patterns of mutation burden (lowest: sarcoma [2.5]; highest: esophagus, germ cell tumor, skin non-melanoma, vaginal [7]). The number of prior therapies did not correlate with the number of genetic alterations (Pearson r = -0.037). The clinical benefit rate was 15.1% ( n = 22). An additional patient had an unconfirmed complete response. The most common adverse events were fatigue, nausea, hyperglycemia, decreased appetite, and diarrhea. Patient and Methods: In this phase 2, open-label, single-arm study, patients with solid or hematologic malignancies with PI3K pathway activation and progression on or after standard treatment received buparlisib (100 mg once daily). The primary endpoint was clinical benefit rate per local investigator assessment (response or stable disease at ≥16 weeks). Conclusions: Buparlisib was well tolerated, however efficacy was limited despite selection of PI3K pathway aberrations. Future studies may provide insight into buparlisib efficacy by refining the molecular selection of different tumor types., Competing Interests: CONFLICTS OF INTEREST S.A. Piha-Paul reports receiving research funding for their institution from AbbVie, Curis, Five Prime Therapeutics, Genmab, GSK, Helix Pharma, Incyte, MedImmune, Merck, NewLink Genetics, Novartis, Pfizer, Pieris, Principia Biopharma, Puma Biotechnology, Tesaro, and XuanZhu Pharma. M.H. Taylor reports receiving honoraria from ArQule, Array Biopharma, Blue Print Medicines, Bristol-Myers Squibb, Eisai Inc., Loxo Oncology, Trillium, and Novartis; consultancy/advisory role for ArQule, Array Biopharma, Blue Print Medicines, Bristol-Myers Squibb, Eisai Inc., Loxo Oncology, and Novartis; speakers’ bureau participation for Bristol-Myers Squibb and Eisai Inc.; and travel, accommodations, or expenses from Array Biopharma, Blue Print Medicines, Bristol-Myers Squibb, Eisai Inc., Loxo Oncology, and Novartis. D. Spitz reports research funding from Florida Cancer Specialists/Sarah Cannon Research. L. Schwartzberg reports consulting/advisory role for Helsinn, Heron, Merck, and Tesaro, and research funding from Helsinn. J.T. Beck reports no potential conflicts of interest to disclose. T.M. Bauer reports consultancy/advisory role for Guardant Health, Ignyta, Loxo Oncology, Moderna Therapeutics, and Pfizer; and receiving research funding for their institution from AbbVie, Aileron Therapeutics, Amgen, Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Calithera Biosciences, Daiichi Sankyo, Deciphera, Five Prime Therapeutics, Genentech, GlaxoSmithKline, Ignyta, Immunocore, Immunogen, Incyte, Jacobio, Kolltan Pharmaceuticals, Leap Therapeutics, Lilly, MabVax, MedImmune, Medpacto Inc., Merck, Merrimack, Millennium, Mirati Therapeutics, Moderna Therapeutics, Novartis, Pfizer, Principa Biopharma, Peleton, Roche, Sanofi, and Stemline Therapeutics. F. Meric-Bernstam reports consulting role for Aduro BioTech, Dialectica, Jackson Laboratory, OrigiMed, Pieris, Samsung Bioepis, Sumitomo Dianippon, and Xencor; advisory role for Clearlight Diagnostics, Darwin Health, GRAIL, Inflection Biosciences, Mersana, and Spectrum; receiving research funding from AbbVie, Aileron, AstraZeneca, Bayer, Calithera Biosciences, Curis, CytomX, Daiichi Sankyo, eFFECTOR, Guardant Health, Jounce, Novartis, Millennium, Puma Biotechnology, Takeda, and Zymeworks; and travel, accommodations, or expenses from Debiopharm Group, Genentech, Pfizer, and Taiho. D. Purkayastha, L. Karpiak, and S. Szpakowski report employment by, and stock ownership of Novartis. S. Szpakowski reports employment of an immediate family member by Compass Therapeutics. F. Braiteh reports receiving honoraria from Amgen, AstraZeneca, Bristol-Myers Squibb, Genentech, Incyte, Merck, and Pfizer; consulting/advisory role for Amgen, AstraZeneca, Eisai, Exelixis, Genentech, and Pfizer; speakers’ bureau participation for Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene, Genentech, Incyte, Lilly, Pfizer, and Puma Biotechnology; and travel, accommodations, or expenses from Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene, Eisai, Exelixis, Genentech, Incyte, Lilly, Pfizer, and Puma Biotechnology., (Copyright: © 2019 Piha-Paul et al.)

Background: In the Mammary Oncology Assessment of LEE011's (Ribociclib's) Efficacy and Safety (MONALEESA-2) study, combination treatment with the selective inhibitor of cyclin-dependent kinases 4/6 ribociclib with letrozole significantly improved progression-free survival (PFS) versus letrozole alone in postmenopausal women with hormone receptor-positive HR + /HER2 - advanced breast cancer (ABC). Herein we present results from the subset of US patients enrolled in MONALEESA-2., Patients and Methods: Postmenopausal women with HR + /HER2 - ABC without previous treatment for advanced disease were randomized (1:1) to ribociclib 600 mg/d (3 weeks on/1 week off) with letrozole 2.5 mg/d (continuous) or placebo with letrozole. The primary end point was locally assessed PFS., Results: Overall, 213 US patients were enrolled in MONALEESA-2 (ribociclib, n = 100; placebo, n = 113). Baseline characteristics were similar between treatment groups and consistent with the global population. With a median follow-up of 27 months, 38 (38%) and 29 (26%) patients in the ribociclib and placebo groups, respectively, had continued to receive treatment. Median PFS was 27.6 months with ribociclib and 15.0 months with placebo (hazard ratio, 0.53). The most common all-cause adverse events were neutropenia (ribociclib, 72.0% [n = 72]; placebo, 4.6% [n = 5]), nausea (ribociclib, 69.0% [n = 69]; placebo, 44.0% [n = 48]), and fatigue (ribociclib, 60.0% [n = 60]; placebo, 50.5% [n = 55]). Two patients (ribociclib, 2.0%; placebo, 0%) experienced febrile neutropenia., Conclusion: In the US subset of MONALEESA-2, ribociclib with letrozole showed superior efficacy versus letrozole alone. These findings are consistent with the global population and support first-line use of ribociclib with letrozole in patients with HR + /HER2 - ABC., (Copyright © 2019. Published by Elsevier Inc.)

Rationale: Roflumilast reduces exacerbations in patients with severe chronic obstructive pulmonary disease associated with chronic bronchitis and a history of exacerbations. Further characterization of patients most likely to benefit is warranted., Objectives: Define characteristics that most robustly identify patients who derive greatest exacerbation risk reduction with roflumilast., Methods: Predefined, pooled analyses of REACT (Roflumilast in the Prevention of COPD Exacerbations While Taking Appropriate Combination Treatment; NCT01329029) and RE 2 SPOND (Roflumilast Effect on Exacerbations in Patients on Dual [LABA/ICS] Therapy; NCT01443845) multicenter, randomized, double-blind, placebo-controlled studies. The primary endpoint was rate of moderate or severe exacerbations per patient per year., Measurements and Main Results: In the overall intention-to-treat population (n = 4,287), roflumilast reduced moderate or severe exacerbations by 12.3% (rate ratio, 0.88, 95% confidence interval, 0.80-0.97; P = 0.0086) and severe exacerbations by 16.1% (0.84; 0.71-0.99; P = 0.0409) versus placebo. The reduction in moderate or severe exacerbations with roflumilast was most pronounced in patients who had been hospitalized for an exacerbation in the prior year (0.74; 0.63-0.88; P = 0.0005); had more than two exacerbations in the prior year (0.79; 0.65-0.96; P = 0.0160); or had baseline eosinophils ≥150 cells/μl (0.81; 0.71-0.93; P = 0.0020), ≥150 to <300 cells/μl (0.84; 0.71-0.98; P = 0.0282), or ≥300 cells/μl (0.77; 0.61-0.97; P = 0.0264). Similar subgroup results were noted for severe exacerbations. In patients with prior hospitalization and higher baseline blood eosinophil concentrations, roflumilast reduced moderate or severe exacerbations by 34.5% at ≥150 cells/μl (0.65; 0.52-0.82; P = 0.0003) and 42.7% at ≥300 cells/μl (0.57; 0.37-0.88; P = 0.0111) versus placebo., Conclusions: This prespecified, pooled analysis confirms the benefit of roflumilast in decreasing exacerbations in patients with prior hospitalization for exacerbation, greater exacerbation frequency, and higher (≥150 cells/μl, ≥150 to <300 cells/μl, or ≥300 cells/μl) baseline blood eosinophil count.

Background: The clinical effects of roflumilast, a selective phosphodiesterase-4 inhibitor, are well established, but little is known about the anti-inflammatory mechanisms underlying the drug's efficacy. The aim of the ROflumilast Biopsy European Research Trial (ROBERT) was to assess the anti-inflammatory effects of roflumilast on bronchial mucosal inflammation in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) and chronic bronchitis., Methods: ROBERT was a randomised, double-blind, placebo-controlled trial done at 18 sites in five countries. Eligible patients were aged 40-80 years, had COPD, and had had a chronic productive cough for 3 months in each of the two previous years. Patients also had to have a post-bronchodilator predicted FEV 1 30-80% and a post-bronchodilator FEV 1 /forced vital capacity ratio of 70% or less. Patients entered a 6-week run-in period before being randomly assigned (1:1) via a computerised central randomisation system to roflumilast 500 μg once daily or placebo for 16 weeks, in addition to bronchodilator therapy (inhaled corticosteroids were not permitted). Randomisation was stratified by concomitant use of long-acting β agonist. Both participants and investigators were masked to group assignment. Roflumilast and placebo were supplied as identical yellow, triangular tablets. Airway inflammation was assessed by quantification of inflammatory cells in bronchial biopsy samples and induced sputum samples. The primary endpoint was the change in the number of CD8 inflammatory cells in bronchial biopsy submucosa from randomisation to week 16 in the intention-to-treat population. Changes in cell counts of additional inflammatory markers, including eosinophils, were assessed as secondary endpoints. This trial is registered with ClinicalTrials.gov, number NCT01509677, and is closed to new participants, with follow-up completed., Findings: Between Jan 4, 2012, and Feb 11, 2016, 158 patients were randomly assigned: 79 to the roflumilast group, and 79 to the placebo group. At week 16, the change in the number of CD8 cells in the bronchial submucosa did not differ significantly between the roflumilast and placebo groups (treatment ratio 1·03 [95% CI 0·82-1·30]; p=0·79). However, compared with placebo, roflumilast was associated with a significant reduction in eosinophils in bronchial biopsy samples at week 16 (treatment ratio 0·53 [95% CI 0·34-0·82]; p=0·0046). Significant reductions in both absolute (p=0·0042) and differential (p=0·0086) eosinophil cell counts in induced sputum were also noted with roflumilast compared with placebo, but peripheral blood eosinophil counts were not significantly affected. We noted no other significant effects of roflumilast on bronchial mucosal inflammatory cells. The most common (ie, occurring in >5% patients) moderate adverse events were worsening of COPD (three [4%] patients in the roflumilast group vs seven [9%] in the placebo group), cough (six [8%] vs four [5%]), diarrhoea (four [5%] vs three [4%]), and nasopharyngitis (three [4%] vs five [6%]). Severe adverse events included worsening of COPD, which occurred in four (5%) patients in the roflumilast group and two (3%) in the placebo group. No deaths occurred during the study. Serious adverse events occurred in eight (10%) patients in the roflumilast group and five (6%) in the placebo group., Interpretation: 16 weeks of treatment with roflumilast did not affect the number of CD8 cells in bronchial submucosa compared with placebo. However, we noted significant reductions in eosinophil cell counts in bronchial biopsy samples and induced sputum, generating the hypothesis that the effect of roflumilast in COPD could be mediated by an effect on lung eosinophils., Funding: Takeda and AstraZeneca., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Breast cancer is the leading cause of cancer death among women worldwide. In India, the incidence rate of breast cancer is found to be 25.8/10,000 females. The statistics for Kerala, India, is 30.5 in urban areas and 19.8 in rural areas. Cancer and treatment-related symptoms are major stressors in patients with breast cancer undergoing treatment for the disease. Depression is a prevalent psychological symptom perceived by breast cancer patients, and it also impacts the quality of life (QOL) in these patients. We aimed to assess the prevalence of depression and its association with QOL of patients with breast cancer undergoing treatment for breast cancer., Materials and Methods: This cross-sectional study enrolled 270 patients diagnosed with breast cancer (>18 years) and undergoing active treatment in a tertiary care center in Kerala, India. Depression was assessed using the Patient Health Questionnaire 9 and International Classification of Diseases, Tenth Edition Research guidelines. We measured the QOL and its domains using the WHOQOL-BREF., Results: The average age of women in research was 53.56 years. Of the 270 patients, 21.5% had depression. Among patients with depression, 22% had moderately severe to severe depression. Patients with depression experienced overall a poor QOL. Twenty-two patients reported their overall QOL was "poor" and 34 patients reported to be dissatisfied with their health. There was an association between depression and domains of QOL. Patients with depression had lower scores in all domains when compared to those without depression., Conclusion: Depression and poor QOL is common among breast cancer patients., Competing Interests: There are no conflicts of interest.

Background: Gastrointestinal stromal tumours (GISTs) are the most common gastrointestinal sarcomas. This global, prospective registry followed patients with advanced or localised GIST (2007-2011)., Methods: Current and evolving diagnostics, treatments and outcome measures in patients with GIST were assessed. Eligible patients were diagnosed with advanced or localised GIST within 15months of registry entry. No treatment plan was prescribed, and no visit schedule was mandated. Treating physicians recorded patient information, including tumour response, diagnostic methods, medications, surgeries performed, mutation status and adverse events leading to dose/medication changes. Survival outcomes were estimated using the Kaplan-Meier method. Other data were analysed using descriptive statistics., Results: The registry included 1663 patients (advanced GIST, n=1095; localised GIST, n=537). Medications (e.g. tyrosine kinase inhibitor use and dosing), disease progression or recurrence and physician assessment of response to treatment in registry patients were consistent with controlled trials and prevailing clinical recommendations. In advanced GIST, estimated 30-month progression-free survival (PFS) (59.8%) and overall survival (OS) (82.7%) were higher than results from previously reported trials (≈40% and ≈70%, respectively). Consistent with treatment guidelines, the most common initial treatments were imatinib for advanced GIST, and complete surgical resection for localised GIST. Computed tomography scans were the most common imaging technique used at diagnosis and follow-up. Mutation analysis was performed at diagnosis in only 15.3% and 14.5% of patients with advanced and localised GIST, respectively., Conclusions: In this real-world GIST registry, patients with advanced GIST were treated with imatinib and patients with localised GIST received surgical resection, in accordance with prevailing clinical recommendations., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)