Online and Offline Prioritization of Chemicals of Interest in Suspect Screening and Non-targeted Screening with High-Resolution Mass Spectrometry.

Recent advances in high-resolution mass spectrometry (HRMS) have enabled the detection of thousands of chemicals from a single sample, while computational methods have improved the identification and quantification of these chemicals in the absence of reference standards typically required in targeted analysis. However, to determine the presence of chemicals of interest that may pose an overall impact on ecological and human health, prioritization strategies must be used to effectively and efficiently highlight chemicals for further investigation. Prioritization can be based on a chemical's physicochemical properties, structure, exposure, and toxicity, in addition to its regulatory status. This Perspective aims to provide a framework for the strategies used for chemical prioritization that can be implemented to facilitate high-quality research and communication of results. These strategies are categorized as either "online" or "offline" prioritization techniques. Online prioritization techniques trigger the isolation and fragmentation of ions from the low-energy mass spectra in real time, with user-defined parameters. Offline prioritization techniques, in contrast, highlight chemicals of interest after the data has been acquired; detected features can be filtered and ranked based on the relative abundance or the predicted structure, toxicity, and concentration imputed from the tandem mass spectrum (MS2). Here we provide an overview of these prioritization techniques and how they have been successfully implemented and reported in the literature to find chemicals of elevated risk to human and ecological environments. A complete list of software and tools is available from https://nontargetedanalysis.org/.

Adverse Events Associated With Treatment for Pan-Susceptible Tuberculosis in San Francisco.

Of 373 patients treated for drug-susceptible tuberculosis, 35.4% (46.2% aged ≥65 years) developed moderate/severe adverse events that required treatment interruption (34.8%), first-line drug discontinuation (26.2%, primarily pyrazinamide), second-line drug initiation (30.0%), and treatment duration up to 3.8 months longer. More safe and effective options are needed, including for the elderly.

Demonstrating the Use of Non-targeted Analysis for Identification of Unknown Chemicals in Rapid Response Scenarios.

Several thousand intentional and unintentional chemical releases occur annually in the U.S., with the contents of almost 30% being of unknown composition. When targeted methods are unable to identify the chemicals present, alternative approaches, including non-targeted analysis (NTA) methods, can be used to identify unknown analytes. With new and efficient data processing workflows, it is becoming possible to achieve confident chemical identifications via NTA in a timescale useful for rapid response (typically 24-72 h after sample receipt). To demonstrate the potential usefulness of NTA in rapid response situations, we have designed three mock scenarios that mimic real-world events, including a chemical warfare agent attack, the contamination of a home with illicit drugs, and an accidental industrial spill. Using a novel, focused NTA method that utilizes both existing and new data processing/analysis methods, we have identified the most important chemicals of interest in each of these designed mock scenarios in a rapid manner, correctly assigning structures to more than half of the 17 total features investigated. We have also identified four metrics (speed, confidence, hazard information, and transferability) that successful rapid response analytical methods should address and have discussed our performance for each metric. The results reveal the usefulness of NTA in rapid response scenarios, especially when unknown stressors need timely and confident identification.

Nivolumab/Relatlimab: A Novel Addition to Immune Checkpoint Inhibitor Therapy in Unresectable or Metastatic Melanoma.

OBJECTIVE: The aim of this article is to assess available data regarding use of nivolumab/relatlimab for adult and pediatric patients 12 years of age and older with unresectable or metastatic melanoma. DATA SOURCES: A search of PubMed conducted from August 2019 to August 2022 with the search terms Opdualag, nivolumab AND relatlimab, and BMS-986016 resulted in 14 publications. STUDY SELECTION AND DATA EXTRACTION: Relevant clinical trials written in English language were analyzed. DATA SYNTHESIS: Nivolumab/relatlimab was approved by the Food and Drug Administration following results of a phase 1/2 trial and phase 2/3 RELATIVITY-047 trial. Nivolumab/relatlimab demonstrated a median progression free survival (PFS) of 10.1 months in the first-line setting without new safety signals. The PFS benefits appear greatest in those with programmed cell death-ligand 1 (PD-L1) <1% and lymphocyte activation gene-3 (LAG-3) ≥1%. Adverse effects commonly experienced were immune related in nature and require early identification and prompt management. Grade 3 or 4 adverse effects occurred in 18.9% of patients. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: For patients 12 years of age and older with unresectable or metastatic melanoma, nivolumab/relatlimab offers a new first-line treatment option. Evaluation of PD-L1 expression along with concomitant use of medications with potential interactions should be evaluated when deciding if nivolumab/relatlimab is the most appropriate treatment option. CONCLUSIONS: Nivolumab/relatlimab adds an additional first-line treatment option demonstrating promising improved PFS for patients with unresectable or metastatic melanoma, particularly those with PD-L1 <1% and/or LAG 3 ≥1%. Additional uses of nivolumab/relatlimab may be on the horizon as further clinical trials are ongoing.

Impact of diabetes (type 2) and glycemic control on health-related outcomes of patients receiving chemotherapy for non-metastatic breast cancer: a retrospective analysis.

PURPOSE: To examine the impact of diabetes (type 2) and glycemic control on healthcare-related outcomes (healthcare utilization, adverse effects, and treatment modifications) in non-metastatic breast cancer (NMBC) patients during chemotherapy treatment. METHODS: This was a retrospective study of 243 NMBC patients (stages 1-3) with/without diabetes receiving neoadjuvant or adjuvant cytotoxic chemotherapy. The primary study endpoint was to compare healthcare utilization between NMBC patients with and without diabetes. Secondary study endpoints included adverse events and chemotherapy treatment modifications. Additional analyses were conducted to compare these health-related outcomes by glycemic control status. RESULTS: NMBC patients with diabetes had higher utilization of emergency department (ED) services (52% vs. 33%, p = 0.013) and a higher frequency of unplanned inpatient admissions (35% vs. 19%, p = 0.014). Additionally, NMBC patients with diabetes had a higher incidence of infection and treatment modifications. NMBC patients, regardless of diabetes diagnosis, who had poor glycemic control, specifically hyperglycemia (per random blood glucose), during the study period also had increased healthcare utilization, adverse effects, and treatment modifications. Patients with a baseline HbA1c ≥ 7 had a greater number of ED visits and a higher incidence of infection than those without diabetes. CONCLUSION: Diabetes and glycemic control may impact the health-related outcomes of NMBC patients. Additional studies are needed to confirm these findings and determine optimal monitoring and management strategies for NMBC patients with diabetes and/or poor glycemic control during cytotoxic chemotherapy.

Associations Among Clinical Factors and Occupational Therapy Service Utilization in Children With Autism Spectrum Disorder.

IMPORTANCE: Limited research has elucidated factors predicting occupational therapy-specific service utilization by children with autism. Such research is needed to inform reasons for receipt of services. OBJECTIVE: To examine factors associated with occupational therapy service utilization by children with autism. We hypothesized that elevated sensory hyperresponsiveness; greater sensory interests, repetitions, and seeking; and lower adaptive behavior would predict more service utilization. DESIGN: Analysis of extant data from a prospective, longitudinal survey study about autism symptom severity, adaptive behavior, sensory features, and demographic and service utilization information of children with autism ages 3 to 13 yr. SETTING: Online parent survey regarding child behaviors during daily activities and contexts. PARTICIPANTS: 892 parents of children with autism from 50 U.S. states. OUTCOMES AND MEASURES: We used scores on the Vineland Adaptive Behavior Scale-Second Edition, the Social Responsiveness Scale, and the Sensory Experiences Questionnaire Version 3.0 and responses to a demographic questionnaire. We formulated hypotheses after data collection but before analysis. RESULTS: Predictors of higher occupational therapy service utilization were lower enhanced perception; lower adaptive behavior; elevated sensory interests, repetitions, and seeking behaviors; younger child age; and higher household income. CONCLUSION AND RELEVANCE: Results partially support our hypotheses. Sensory interests, repetitions, and seeking behavior predicted occupational therapy service utilization, whereas other sensory response patterns did not, suggesting a possible referral bias for certain sensory response patterns. Occupational therapy practitioners can educate parents and teachers about the scope of practice, which includes addressing sensory features beyond sensory interests, repetitions, and seeking behaviors. What This Article Adds: Children with autism who have impairments in adaptive functioning and high levels of sensory interests, repetitions, and seeking behaviors receive more occupational therapy services. Occupational therapy practitioners should be well trained to address such concerns and advocate for the profession's role in mitigating the impact of sensory features on daily life.

Outcomes and Management of Immune Checkpoint Inhibitor-Induced Hypothyroidism: A Retrospective Analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) used in cancer treatment cause immune-related adverse effects (irAEs), including thyroiditis leading to hypothyroidism. The management and outcomes of this irAE are not well established. OBJECTIVE: The purpose of this analysis is to describe the onset, management, and outcomes of patients experiencing hypothyroidism from ICI. METHODS: A retrospective study was conducted of adults receiving ICI therapy at a community cancer center between January 1, 2017, and February 1, 2020. The primary endpoint was to describe onset (timing) of hypothyroidism (thyroid-stimulating hormone [TSH] > 10 µIU/mL). Secondary outcomes included describing hypothyroidism symptoms and levothyroxine use, time to documented disease progression, and occurrence of additional adverse effects (AEs). RESULTS: Of the 200 patients included in the study, 19% developed clinical hypothyroidism (TSH > 10 µIU/mL, or required initiation of or dose increase in levothyroxine). Median time to TSH higher than 10 µIU/mL was 13.3 weeks and symptoms of hypothyroidism occurred in 34% of patients developing clinical hypothyroidism. The median final daily levothyroxine dose was 88 mcg (0.88 mcg/kg). Time to disease progression was longer in those with clinical hypothyroidism (27.4 months vs. 6.8 months, respectively, P = .015). Additional AEs occurred in 68% of those developing hypothyroidism versus 49% without hypothyroidism (P = .029). CONCLUSION AND RELEVANCE: Patients with clinical hypothyroidism during ICI treatment may have improved cancer outcomes, but they also are more likely to develop other AEs. Patients requiring thyroid replacement therapy with levothyroxine may benefit from a starting dose between 50 and 100 mcg/day, approximately 0.88 mcg/kg/day.

Persistent autism-relevant behavioral phenotype and social neuropeptide alterations in female mice offspring induced by maternal transfer of PBDE congeners in the commercial mixture DE-71.

Polybrominated diphenyl ethers (PBDEs) are ubiquitous persistent organic pollutants (POPs) that are known neuroendocrine disrupting chemicals with adverse neurodevelopmental effects. PBDEs may act as risk factors for autism spectrum disorders (ASD), characterized by abnormal psychosocial functioning, although direct evidence is currently lacking. Using a translational exposure model, we tested the hypothesis that maternal transfer of a commercial mixture of PBDEs, DE-71, produces ASD-relevant behavioral and neurochemical deficits in female offspring. C57Bl6/N mouse dams (F0) were exposed to DE-71 via oral administration of 0 (VEH/CON), 0.1 (L-DE-71) or 0.4 (H-DE-71) mg/kg bw/d from 3 wk prior to gestation through end of lactation. Mass spectrometry analysis indicated in utero and lactational transfer of PBDEs (in ppb) to F1 female offspring brain tissue at postnatal day (PND) 15 which was reduced by PND 110. Neurobehavioral testing of social novelty preference (SNP) and social recognition memory (SRM) revealed that adult L-DE-71 F1 offspring display deficient short- and long-term SRM, in the absence of reduced sociability, and increased repetitive behavior. These effects were concomitant with reduced olfactory discrimination of social odors. Additionally, L-DE-71 exposure also altered short-term novel object recognition memory but not anxiety or depressive-like behavior. Moreover, F1 L-DE-71 displayed downregulated mRNA transcripts for oxytocin (Oxt) in the bed nucleus of the stria terminalis (BNST) and supraoptic nucleus, and vasopressin (Avp) in the BNST and upregulated Avp1ar in BNST, and Oxtr in the paraventricular nucleus. Our work demonstrates that developmental PBDE exposure produces ASD-relevant neurochemical, olfactory processing and behavioral phenotypes that may result from early neurodevelopmental reprogramming within central social and memory networks.

Nontargeted Analysis Study Reporting Tool: A Framework to Improve Research Transparency and Reproducibility.

Non-targeted analysis (NTA) workflows using mass spectrometry are gaining popularity in many disciplines, but universally accepted reporting standards are nonexistent. Current guidance addresses limited elements of NTA reporting-most notably, identification confidence-and is insufficient to ensure scientific transparency and reproducibility given the complexity of these methods. This lack of reporting standards hinders researchers' development of thorough study protocols and reviewers' ability to efficiently assess grant and manuscript submissions. To overcome these challenges, we developed the NTA Study Reporting Tool (SRT), an easy-to-use, interdisciplinary framework for comprehensive NTA methods and results reporting. Eleven NTA practitioners reviewed eight published articles covering environmental, food, and health-based exposomic applications with the SRT. Overall, our analysis demonstrated that the SRT provides a valid structure to guide study design and manuscript writing, as well as to evaluate NTA reporting quality. Scores self-assigned by authors fell within the range of peer-reviewer scores, indicating that SRT use for self-evaluation will strengthen reporting practices. The results also highlighted NTA reporting areas that need immediate improvement, such as analytical sequence and quality assurance/quality control information. Although scores intentionally do not correspond to data/results quality, widespread implementation of the SRT could improve study design and standardize reporting practices, ultimately leading to broader use and acceptance of NTA data.

An Introduction to the Benchmarking and Publications for Non-Targeted Analysis Working Group.

Non-targeted analysis (NTA) encompasses a rapidly evolving set of mass spectrometry techniques aimed at characterizing the chemical composition of complex samples, identifying unknown compounds, and/or classifying samples, without prior knowledge regarding the chemical content of the samples. Recent advances in NTA are the result of improved and more accessible instrumentation for data generation and analysis tools for data evaluation and interpretation. As researchers continue to develop NTA approaches in various scientific fields, there is a growing need to identify, disseminate, and adopt community-wide method reporting guidelines. In 2018, NTA researchers formed the Benchmarking and Publications for Non-Targeted Analysis Working Group (BP4NTA) to address this need. Consisting of participants from around the world and representing fields ranging from environmental science and food chemistry to 'omics and toxicology, BP4NTA provides resources addressing a variety of challenges associated with NTA. Thus far, BP4NTA group members have aimed to establish a consensus on NTA-related terms and concepts and to create consistency in reporting practices by providing resources on a public Web site, including consensus definitions, reference content, and lists of available tools. Moving forward, BP4NTA will provide a setting for NTA researchers to continue discussing emerging challenges and contribute to additional harmonization efforts.

In Vitro Metabolism of Isopropylated and tert-Butylated Triarylphosphate Esters Using Human Liver Subcellular Fractions.

Isopropylated and tert-butylated triarylphosphate esters (ITPs and TBPPs, respectively) are plasticizers and flame retardants that are ubiquitous in indoor environments; however, no studies to date have characterized their metabolism. Using human liver subcellular S9 fractions, phase I and II in vitro metabolism of triphenyl phosphate (TPHP), 4-tert-butylphenyl diphenyl phosphate (4tBPDPP), 2-isopropylphenyl diphenyl phosphate (2IPPDPP), and 4-isopropylphenyl diphenyl phosphate (4IPPDPP) was investigated at 1 and 10 µM doses. Parent depletion and the formation of known or suspected metabolites (e.g., likely hydrolysis or hydroxylated products), including diphenyl phosphate (DPHP), hydroxyl-triphenyl phosphate (OH-TPHP), isopropylphenyl phenyl phosphate (ip-PPP), and tert-butylphenyl phenyl phosphate (tb-PPP), were monitored and quantified via GC/MS or LC-MS/MS. tb-PPP and its conjugates were identified as the major in vitro metabolites of 4tBPDPP and accounted for 71% and 49%, respectively, of the parent molecule that was metabolized during the incubation. While the mass balance between parents and metabolites was conserved for TPHP and 4tBPDPP, approximately 20% of the initial parent mass was unaccounted for after quantifying suspected metabolites of 2IPPDPP and 4IPPDPP that had authentic standards available. Two novel ITP metabolites, mono-isopropenylphenyl diphenyl phosphate and hydroxy-isopropylphenyl diphenyl phosphate, were tentatively identified by high-resolution mass spectrometry and screened for in recently collected human urine where mono-isopropenylphenyl diphenyl phosphate was detected in one of nine samples analyzed. This study provides insight into the biological fate of ITP and TBPP isomers in human tissues and is useful in identifying appropriate biomarkers of exposure to monitor, particularly in support of epidemiological studies.

Comparing the Use of Silicone Wristbands, Hand Wipes, And Dust to Evaluate Children's Exposure to Flame Retardants and Plasticizers.

Organophosphate esters (OPEs) are applied as additive flame retardants, and along with phthalates, are also used as plasticizers in consumer products. As such, human exposure is common and chronic. Deployed as personal passive samplers, silicone wristbands have been shown to detect over a thousand industrial and consumer product chemicals; however, few studies have evaluated chemical concentrations with their corresponding biomarkers of exposure, especially in children. Further, little is known about how well the wristbands predict individual exposure compared to existing validated external exposure tools such as indoor air, dust, and hand wipes. Here, we analyzed wristbands worn by children (ages 3-6) for 18 OPEs and 10 phthalates and compared them to corresponding urinary biomarkers. In wristbands, 13 of 18 OPEs and all phthalates were detected in >80% of wristbands, and 6 OPEs and 4 phthalates were significantly associated with corresponding urinary metabolites (rs = 0.2-0.6, p < 0.05). When compared to paired hand wipes and house dust, wristbands were found to have similar or greater correlation coefficients with respective urinary biomarkers. These results suggest that wristbands can serve as effective and quantitative assessment tools for evaluating personal exposure to some OPEs and phthalates, and for certain chemicals, may provide a better exposure estimate than indoor dust.

Per- and Polyfluoroalkyl Substances in Dust Collected from Residential Homes and Fire Stations in North America.

Over the past few years, human exposure to per- and polyfluoroalkyl substances (PFAS) has garnered increased attention. Research has focused on PFAS exposure via drinking water and diet, and fewer studies have focused on exposure in the indoor environment. To support more research on the latter exposure pathway, we conducted a study to evaluate PFAS in indoor dust. Dust samples from 184 homes in North Carolina and 49 fire stations across the United States and Canada were collected and analyzed for a suite of PFAS using liquid and gas chromatography-mass spectrometry. Fluorotelomer alcohols (FTOHs) and di-polyfluoroalkyl phosphoric acid esters (diPAPs) were the most prevalent PFAS in both fire station and house dust samples, with medians of approximately 100 ng/g dust or greater. Notably, perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonate, perfluorononanoic acid, and 6:2 diPAP were significantly higher in dust from fire stations than from homes, and 8:2 FTOH was significantly higher in homes than in fire stations. Additionally, when comparing our results to earlier published values, we see that perfluoroalkyl acid levels in residential dust appear to decrease over time, particularly for PFOA and PFOS. These results highlight a need to better understand what factors contribute to PFAS levels in dust and to understand how much dust contributes to overall human PFAS exposure.

Evaluating the Use of Silicone Wristbands To Measure Personal Exposure to Brominated Flame Retardants.

Biomarkers remain the gold standard for assessing chemical exposure. However, silicone wristbands may provide some added benefits for characterizing personal exposures compared to single biomarker measurements, such as decreased costs, noninvasive sampling, and increased ease of analysis. Previously, we validated their use in characterizing exposure to organophosphate flame retardants (PFRs). However, it is unclear whether these results would extend to chemicals like polybrominated diphenyl ethers (PBDEs), which biomagnify and have longer half-lives than PFRs in the body. This study sought to determine if accumulation of PBDEs on wristbands was correlated to serum biomarkers. Adult participants ( n = 30) provided serum samples and wore wristbands for 7 days. PBDEs and 6 novel brominated flame retardants (BFRs) were measured on wristbands, and serum samples were analyzed for PBDE biomarkers. Like most PBDE congeners, 5 of 6 novel BFRs were frequently detected on wristbands (≥90% of bands). In particular, decabromodiphenyl ethane (DBDPE) was detected in all wristbands in this study and was significantly correlated with BDE-209, suggesting a similar source and exposure pathway. Wristband levels of BDE-47, -99, -100, and -153 were significantly and positively associated with respective serum biomarkers ( rs = 0.39-0.57, p < 0.05). This study demonstrates that silicone wristbands can accurately detect personal PBDE exposures.

Ranking Coal Ash Materials for Their Potential to Leach Arsenic and Selenium: Relative Importance of Ash Chemistry and Site Biogeochemistry.

The chemical composition of coal ash is highly heterogeneous and dependent on the origin of the source coal, combustion parameters, and type and configuration of air pollution control devices. This heterogeneity results in uncertainty in the evaluation of leaching potential of contaminants from coal ash. The goal of this work was to identify whether a single leaching protocol could roughly group high-leaching potential coal ash from low-leaching potential coal ash, with respect to arsenic (As) and selenium (Se). We used four different leaching tests, including the Toxicity Characteristic Leaching Protocol (TCLP), natural pH, aerobic sediment microcosms, and anaerobic sediment microcosms on 10 different coal ash materials, including fly ash, lime-treated ash, and flue gas desulfurization materials. Leaching tests showed promise in categorizing high and low-leaching potential ash materials, indicating that a single point test could act as a first screening measure to identify high-risk ash materials. However, the amount of contaminant leached varied widely across tests, reflecting the importance of ambient conditions (pH, redox state) on leaching. These results demonstrate that on-site geochemical conditions play a critical role in As and Se mobilization from coal ash, underscoring the need to develop a situation-based risk assessment framework for contamination by coal ash pollutants.

An exploratory study of networks constructed using access data from an electronic health record.

Network analysis may be a powerful tool for studying interprofessional practice. Using electronic health record data and social network analysis, the network of healthcare professionals involved in colorectal cancer care at a large, urban academic medical center were mapped and studied. A total of 100 surgical colorectal cancer patients receiving treatment in 2013 and 2014 were selected at random. We used detailed access logs for the EHR to map the network of all healthcare professionals for each patient, including inpatient and outpatient settings. Approximately 2.45 million records of access logs from more than 6,800 unique users, representing over 150 roles or occupations were analyzed. Across all networks, professionals were connected to an average of 5.8 other professionals, but some were rarely connected with others while over 20 were very highly connected (> 100 other professionals). Housestaff, attending physicians, and nurses played central roles in the global network with a high number of inter- and intra-professional connections. Clusters of professionals with frequent interaction were demonstrated but, based on the size and complexity of the network, serendipitous interactions were unlikely. Settings for care seemed to influence these clusters. Patient-centric care networks were similar to the global network with some potentially important differences. Access-log information from electronic health records can be an important source of information about relationships between healthcare professionals. Findings from analyses such as this one may help define the state of current networks and potential targets for interventions to improve the quality of care.

Change implementation: the association of adaptive reserve and burnout among inpatient medicine physicians and nurses.

Adaptive Reserve (AR) is positively associated with implementing change in ambulatory settings. Deficits in AR may lead to change fatigue or burnout. We studied the association of self-reported AR and burnout among providers to hospitalized medicine patients in an academic medical center. An electronic survey containing a 23-item Adaptive Reserve scale, burnout inventory, and demographic questions was sent to a convenience sample of nurses, house staff team members, and hospitalists. A total of 119 self-administered, online surveys collected from June 2014 to March 2015 were analyzed. Ordinal regression analyses were used to examine the association between AR and burnout. Eighty percent of participants reported either level 1 or 2 burnout. Additionally, 10.9% of participants responded level 0% and 7.6% of participants reported level 3. Participants reporting higher burnout were about three times more likely to report lower AR levels. AR is strongly associated with self-reported burnout by physicians and nurses providing inpatient care at this academic medical center. Growing evidence supports the positive association of AR to successful change implementation in ambulatory settings. Similar studies are needed to determine whether certain levels of AR can predict successful change in hospital settings.

The path to eradication: a progress report on the malaria-eliminating countries.

In the past several years, as worldwide morbidity and mortality due to malaria have continued to decrease, the global malaria community has grown increasingly supportive of the idea of malaria eradication. In 2015, three noteworthy global documents were released-the WHO's Global Technical Strategy for Malaria 2016-2030, the Roll Back Malaria Partnership's Action and Investment to defeat Malaria 2016-2030, and From Aspiration to Action: What Will It Take to End Malaria?-that collectively advocate for malaria elimination and eradication and outline key operational, technical, and financial strategies to achieve progress toward malaria eradication. In light of this remarkable change in global attitudes toward malaria elimination and eradication, and as the malaria community debates how and when to embark on this ambitious goal, it is important to assess current progress along the path to eradication. Although low-income, high-burden countries are often the focus when discussing the substantial challenges of eradication, the progress toward elimination in middle-income, low-burden countries is a major driver of global progress and deserves better recognition. Additionally, although global support and guidance is essential for success, malaria elimination and eradication efforts will ultimately be driven at the country level and achieved in a collaborative manner, region by region. In this Review, we examine the present status of the 35 malaria-eliminating countries, summarise existing national and regional elimination goals and the regional frameworks that support them, and identify the most crucial enabling factors and potential barriers to achieving eradication by a theoretical end date of 2040.

Characterization of Individual Isopropylated and tert-Butylated Triarylphosphate (ITP and TBPP) Isomers in Several Commercial Flame Retardant Mixtures and House Dust Standard Reference Material SRM 2585.

Since the phase-out of pentaBDE in the early 2000s, replacement flame-retardant mixtures including Firemaster 550 (FM 550), Firemaster 600 (FM 600), and organophosphate aryl ester technical mixtures have been increasingly used to treat polyurethane foam in residential upholstered furniture. These mixtures contain isomers of isopropylated and tert-butylated triarylphosphate esters (ITPs and TBPPs), which have similar or greater neuro- and developmental toxicity compared to BDE 47 in high-throughput assays. Additionally, human exposure to ITPs and TBPPs has been demonstrated to be widespread in several recent studies; however, the relative composition of these mixtures has remained largely uncharacterized. Using available authentic standards, the present study quantified the contribution of individual ITP and TBPP isomers in four commercial flame retardant mixtures: FM 550, FM 600, an ITP mixture, and a TBPP mixture. Findings suggest similarities between FM 550 and the ITP mixture, with 2-isopropylphenyl diphenyl phosphate (2IPPDPP), 2,4-diisopropylphenyl diphenyl phosphate (24DIPPDPP), and bis(2-isopropylphenyl) phenyl phosphate (B2IPPPP) being the most prevalent ITP isomers in both mixtures. FM 600 differed from FM 550 in that it contained TBPP isomers instead of ITP isomers. These analytes were also detected and quantified in a house dust standard reference material, SRM 2585, demonstrating their environmental relevance.

Global fund financing to the 34 malaria-eliminating countries under the new funding model 2014-2017: an analysis of national allocations and regional grants.

BACKGROUND: The Global Fund to Fight AIDS, Tuberculosis, and Malaria (GFATM) has been the largest financial supporter of malaria since 2002. In 2011, the GFATM transitioned to a new funding model (NFM), which prioritizes grants to high burden, lower income countries. This shift raises concerns that some low endemic countries, dependent on GFATM financing to achieve their malaria elimination goals, would receive less funding under the NFM. This study aims to understand the projected increase or decrease in national and regional funding from the GFATM's NFM to the 34 malaria-eliminating countries. METHODS: Average annual disbursements under the old funding model were compared to average annual national allocations for all eligible 34 malaria-eliminating countries for the period of 2014-2017. Regional grant funding to countries that are due to receive additional support was then included in the comparison and analysed. Estimated funding ranges for the countries under the NFM were calculated using the proposed national allocation plus the possible adjustments and additional funding. Finally, the minimum and maximum funding estimates were compared to average annual disbursements under the old funding model. RESULTS: A cumulative 31 % decrease in national financing from the GFATM is expected for the countries included in this analysis. Regional grants augment funding for almost half of the eliminating countries, and increase the cumulative percent change in GTFAM funding to 32 %, though proposed activities may not be funded directly through national malaria programmes. However, if countries receive the maximum possible funding, 46 % of the countries included in this analysis would receive less than they received under the previous funding model. CONCLUSIONS: Many malaria-eliminating countries have projected national declines in funding from the GFATM under the NFM. While regional grants enhance funding for eliminating countries, they may not be able to fill country-level funding gaps for local commodities and implementation. If the GFATM is able to nuance its allocation methodology to mitigate drastic funding declines for malaria investments in low transmission countries, the GFATM can ensure previous investments are not lost. By aligning with WHO's Global Technical Strategy for Malaria and investing in both high- and low-endemic countries, the Global Fund can tip the scale on a global health threat and contribute toward the goal of eventual malaria eradication.