Validation of a Stenotrophomonas maltophilia bloodstream infection prediction score in the hematologic malignancy population.

Stenotrophomonas maltophilia (SM) bloodstream infections (BSIs) contribute to significant mortality in hematologic malignancy (HM) and hematopoietic stem cell transplantation (HSCT) patients. A risk score to predict SM BSI could reduce time to appropriate antimicrobial therapy (TTAT) and improve patient outcomes. A single center cohort study of hospitalized adults with HM/HSCT was conducted. Patients had ≥ 1 blood culture with a Gram-negative (GN) organism. A StenoSCORE was calculated for each patient. The StenoSCORE2 was developed using risk factors for SM BSI identified via logistic regression. Receiver operating characteristic (ROC) curves were plotted. Sensitivity and specificity for the StenoSCORE and StenoSCORE2 were calculated. Thirty-six SM patients and 534 non-SM patients were assessed. A StenoSCORE ≥ 33 points was 80% sensitive, 68% specific, and accurately classified 69% of GN BSIs. StenoSCORE2 variables included acute leukemia, prolonged neutropenia, mucositis, ICU admission, recent meropenem and/or cefepime exposure. The StenoSCORE2 performed better than the StenoSCORE (ROC AUC 0.84 vs. 0.77). A StenoSCORE2 ≥ 4 points was 86% sensitive, 76% specific, and accurately classified 77% of GN BSIs. TTAT was significantly longer for patients with SM BSI compared with non-SM BSI (45.16 h vs. 0.57 h; p < 0.0001). In-hospital and 28-day mortality were significantly higher for patients with SM BSI compared to non-SM BSI (58.3% vs. 18.5% and 66.7% vs. 26.4%; p-value < 0.0001). The StenoSCORE and StenoSCORE2 performed well in predicting SM BSIs in patients with HM/HSCT and GN BSI. Clinical studies evaluating whether StenoSCORE and/or StenoSCORE2 implementation improves TTAT and clinical outcomes are warranted.

Mini-Review: Current Bladder Cancer Treatment-The Need for Improvement.

Bladder cancer is the tenth most common cancer and is a significant burden on health care services worldwide, as it is one of the most costly cancers to treat per patient. This expense is due to the extensive treatment and follow-ups that occur with costly and invasive procedures. Improvement in both treatment options and the quality of life these interventions offer has not progressed at the rates of other cancers, and new alternatives are desperately needed to ease the burden. A more modern approach needs to be taken, with urinary biomarkers being a positive step in making treatments more patient-friendly, but there is still a long way to go to make these widely available and of a comparable standard to the current treatment options. New targets to hit the major signalling pathways that are upregulated in bladder cancer, such as the PI3K/AkT/mTOR pathway, are urgently needed, with only one drug approved so far, Erdafitinib. Immune checkpoint inhibitors also hold promise, with both PD-1 and CDLA-4 antibody therapies approved for use. They effectively block ligand/receptor binding to block the immune checkpoint used by tumour cells. Other avenues must be explored, including drug repurposing and novel biomarkers, which have revolutionised this area in other cancers.

Methodologies in Mitochondrial Testing: Diagnosing a Primary Mitochondrial Respiratory Chain Disorder.

BACKGROUND: Mitochondria are cytosolic organelles within most eukaryotic cells. Mitochondria generate the majority of cellular energy in the form of adenosine triphosphate (ATP) through oxidative phosphorylation (OxPhos). Pathogenic variants in mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) lead to defects in OxPhos and physiological malfunctions (Nat Rev Dis Primer 2016;2:16080.). Patients with primary mitochondrial disorders (PMD) experience heterogeneous symptoms, typically in multiple organ systems, depending on the tissues affected by mitochondrial dysfunction. Because of this heterogeneity, clinical diagnosis is challenging (Annu Rev Genomics Hum Genet 2017;18:257-75.). Laboratory diagnosis of mitochondrial disease depends on a multipronged analysis that can include biochemical, histopathologic, and genetic testing. Each of these modalities has complementary strengths and limitations in diagnostic utility. CONTENT: The primary focus of this review is on diagnosis and testing strategies for primary mitochondrial diseases. We review tissue samples utilized for testing, metabolic signatures, histologic findings, and molecular testing approaches. We conclude with future perspectives on mitochondrial testing. SUMMARY: This review offers an overview of the current biochemical, histologic, and genetic approaches available for mitochondrial testing. For each we review their diagnostic utility including complementary strengths and weaknesses. We identify gaps in current testing and possible future avenues for test development.

Long-Term Trends in Secondhand Smoke Exposure in High-Rise Housing Serving Low-Income Residents in New York City: Three-Year Evaluation of a Federal Smoking Ban in Public Housing, 2018-2021.

INTRODUCTION: In July 2018, the U.S. Department of Housing and Urban Development passed a rule requiring public housing authorities to implement smoke-free housing (SFH) policies. We measured secondhand smoke (SHS) exposure immediately before, and repeatedly up to 36 months post-SFH policy implementation in a purposeful sample of 21 New York City (NYC) high-rise buildings (>15 floors): 10 NYC Housing Authority (NYCHA) buildings subject to the policy and 11 privately managed buildings in which most residents received housing vouchers (herein "Section 8"). AIMS AND METHODS: We invited participants from nonsmoking households (NYCHA n = 157, Section-8 n = 118) to enroll in a longitudinal air monitoring study, measuring (1) nicotine concentration with passive, bisulfate-coated filters, and (2) particulate matter (PM2.5) with low-cost particle sensors. We also measured nicotine concentrations and counted cigarette butts in common areas (n = 91 stairwells and hallways). We repeated air monitoring sessions in households and common areas every 6 months, totaling six post-policy sessions. RESULTS: After 3 years, we observed larger declines in nicotine concentration in NYCHA hallways than in Section-8, [difference-in-difference (DID) = -1.92 µg/m3 (95% CI -2.98, -0.87), p = .001]. In stairwells, nicotine concentration declines were larger in NYCHA buildings, but the differences were not statistically significant [DID= -1.10 µg/m3 (95% CI -2.40, 0.18), p = .089]. In households, there was no differential change in nicotine concentration (p = .093) or in PM2.5 levels (p = .385). CONCLUSIONS: Nicotine concentration reductions in NYCHA common areas over 3 years may be attributable to the SFH policy, reflecting its gradual implementation over this time. IMPLICATIONS: Continued air monitoring over multiple years has demonstrated that SHS exposure may be declining more rapidly in NYCHA common areas as a result of SFH policy adherence. This may have positive implications for improved health outcomes among those living in public housing, but additional tracking of air quality and studies of health outcomes are needed. Ongoing efforts by NYCHA to integrate the SFH policy into wider healthier-homes initiatives may increase policy compliance.

Rapid Community Engagement in Response to SARS-CoV-2 Funding Opportunities: New York City, 2020‒2021.

In response to fast-turnaround funding opportunities, collaborations have been forming across the country to address severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disparities. Here we describe the process, notes from the field, and evaluation results from a new collaboration involving multiple partners, formed in October 2020 in New York City as part of the Rapid Acceleration of Diagnostics initiative. We used the validated Research Engagement Survey Tool to evaluate the partnership. Results can inform future research and improve engagement efforts aimed at reducing SARS-CoV-2 disparities. (Am J Public Health. 2022;112(S9):S904-S908. https://doi.org/10.2105/AJPH.2022.307072).

The Sirenic Links between Diabetes, Obesity, and Bladder Cancer.

There is considerable evidence of a positive association between the incidence of type 2 diabetes mellitus (T2DM) and obesity with bladder cancer (BCa), with the link between T2DM and obesity having already been established. There also appear to be potential associations between Pleckstrin homology domain containing S1 (PLEKHS1) and the Insulin-like Growth Factor (IGF) axis. Seven literature searches were carried out to investigate the backgrounds of these potential links. PLEKHS1 is a candidate biomarker in BCa, with mutations that are easily detectable in urine and increased expression seemingly associated with worse disease states. PLEKHS1 has also been implicated as a potential mediator for the onset of T2DM in people with obesity. The substantial evidence of the involvement of IGF in BCa, the role of the IGF axis in obesity and T2DM, and the global prevalence of T2DM and obesity suggest there is scope for investigating the links between these components. Preliminary findings on the relationship between PLEKHS1 and the IGF axis signal possible associations with BCa progression. This indicates that PLEKHS1 plays a role in the pathogenesis of BCa that may be mediated by members of the IGF axis. Further detailed research is needed to establish the relationship between PLEKHS1 and the IGF axis in BCa and determine how these phenomena overlap with T2DM and obesity.

Ultrahigh-Performance Liquid Chromatography-High-Resolution Mass Spectrometry Metabolomics and Lipidomics Study of Stool from Transgenic Parkinson's Disease Mice Following Immunotherapy.

Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta of the brain, as well as the degeneration of motor and nonmotor circuitries. The cause of neuronal death is currently unknown, although chronic neuroinflammation, aggregated α-synuclein, mitochondrial dysfunction, and oxidative stress have all been implicated. Gliosis has been shown to exacerbate neuroinflammation via secretion of proinflammatory cytokines, and there is a subsequent infiltration of T lymphocytes (T-cells), into the brain of PD patients. Using liquid chromatography-high-resolution mass spectrometry (LC-HRMS), we have observed metabolomic changes in stool samples, thought to be associated with the potential disease-modifying effect of immunotherapy administered to transgenic Parkinsonian (A53T) mice. Significant elevations (p < 0.05) in metabolites associated with immune response (taurine, histamine, and its methylated product, 3-methylhistamine) are identified as being higher in the mice undergoing immunotherapy. Furthermore, a reduction in triacylglycerol (TG) and diacylglycerol (DG) expressions in stool following immunotherapy suggests a regulation of lipid breakdown or biosynthesis with the vaccine. These "omics" markers (among others reported in this article) along with weight gain and increased life expectancy suggest that immunotherapy is positively modifying the disease state.

Mass Spectrometric Methodologies for Investigating the Metabolic Signatures of Parkinson's Disease: Current Progress and Future Perspectives.

Parkinson's disease (PD) is a neurodegenerative disorder resulting from the loss of dopaminergic neurons of the substantia nigra as well as degeneration of motor and nonmotor basal ganglia circuitries. Typically known for classical motor deficits (tremor, rigidity, bradykinesia), early stages of the disease are associated with a large nonmotor component (depression, anxiety, apathy, etc.). Currently, there are no definitive biomarkers of PD, and the measurement of dopamine metabolites does not allow for detection of prodromal PD nor does it aid in long-term monitoring of disease progression. Given that PD is increasingly recognized as complex and heterogeneous, involving several neurotransmitters and proteins, it is of importance that we advance interdisciplinary studies to further our knowledge of the molecular and cellular pathways that are affected in PD. This approach will possibly yield useful biomarkers for early diagnosis and may assist in the development of disease-modifying therapies. Here, we discuss preanalytical factors associated with metabolomics studies, summarize current mass spectrometric methodologies used to evaluate the metabolic signature of PD, and provide future perspectives of the rapidly developing field of MS in the context of PD.

Precast Gelatin-Based Molds for Tissue Embedding Compatible with Mass Spectrometry Imaging.

Preparation of tissue for matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) generally involves embedding the tissue followed by freezing and cryosectioning, usually between 5 and 25 µm thick, depending on the tissue type and the analyte(s) of interest. The brain is approximately 60% fat; it therefore lacks rigidity and poses structural preservation challenges during sample preparation. Histological sample preparation procedures are generally transferable to MALDI-MSI; however, there are various limitations. Optimal cutting temperature compound (OCT) is commonly used to embed and mount fixed tissue onto the chuck inside the cryostat during cryosectioning. However, OCT contains potential interferences that are detrimental to MALDI-MSI, while fixation is undesirable for the analysis of some analytes either due to extraction or chemical modification (i.e., polar metabolites). Therefore, a method for both fixed and fresh tissue compatible with MALDI-MSI and histology is desirable to increase the breadth of analyte(s), maintain the topographies of the brain, and provide rigidity to the fragile tissue while eliminating background interference. The method we introduce uses precast gelatin-based molds in which a whole mouse brain is embedded, flash frozen, and cryosectioned in preparation for mass spectrometry imaging (MSI).

Monitoring Dopamine ex Vivo during Electrical Stimulation Using Liquid-Microjunction Surface Sampling.

Liquid-microjunction surface sampling (LMJ-SS) is an ambient ionization technique based on the continuous flow of solvent using an in situ microextraction device in which solvent moves through the probe, drawing in the analytes in preparation for ionization using an electrospray ionization source. However, unlike traditional mass spectrometry (MS) techniques, it operates under ambient pressure and requires no sample preparation, thereby making it ideal for rapid sampling of thicker tissue sections for electrophysiological and other neuroscientific research studies. Studies interrogating neural synapses, or a specific neural circuit, typically employ thick, ex vivo tissue sections maintained under near-physiological conditions to preserve tissue viability and maintain the neural networks. Deep brain stimulation (DBS) is a surgical procedure used to treat the neurological symptoms that are associated with certain neurodegenerative and neuropsychiatric diseases. Parkinson's disease (PD) is a neurological disorder which is commonly treated with DBS therapy. PD is characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta portion of the brain. Here, we demonstrate that the LMJ-SS methodology can provide a platform for ex vivo analysis of the brain during electrical stimulation, such as DBS. We employ LMJ-SS in the ex vivo analysis of mouse brain tissue for monitoring dopamine during electrical stimulation of the striatum region. The mouse brain tissue was sectioned fresh post sacrifice and maintained in artificial cerebrospinal fluid to create near-physiological conditions before direct sampling using LMJ-SS. A selection of metabolites, including time-sensitive metabolites involved in energy regulation in the brain, were identified using standards, and the mass spectral database mzCloud was used to assess the feasibility of the methodology. Thereafter, the intensity of m/z 154 corresponding to protonated dopamine was monitored before and after electrical stimulation of the striatum region, showing an increase in signal directly following a stimulation event. Dopamine is the key neurotransmitter implicated in PD, and although electrochemical detectors have shown such increases in dopamine post-DBS, this is the first study to do so using MS methodologies.

Enzymatic Cross-Linking of Resilin-Based Proteins for Vascular Tissue Engineering Applications.

Protein-based biomaterials have received significant attention for tissue engineering applications. For example, resilin-based protein gels have been produced with different cross-linking chemistries for applications in cartilage, cardiovascular, and vocal fold engineering. In this study, we investigate an alternative cross-linking chemistry to form resilin-based protein hydrogels and demonstrate the versatility of the gels for investigating cell response to matrix stiffness. Specifically, transglutaminase was used to cross-link proteins and resulted in gel surfaces more suitable for long-term cell attachment compared to those formed by a Mannich-type condensation reaction. Since matrix stiffness is an important determinant in modulating cell response, we first tuned matrix stiffness by varying total protein concentration. Next, we observed that matrix stiffness modulated cell spreading and endothelial differentiation of human mesenchymal stem cells. In particular, our results show that cells differentiated on our matrices, which have a stiffness similar to subendothelial layers, had statistically equivalent endothelial function compared to cells differentiated on hard glass surfaces. Thus, our protein-based matrix system is a promising tool to provide substrates favorable for long-term cell attachment and better mimics the native subendothelial environment compared to conventional hard culture substrates.

Development and validation of a dietary screening tool for high sodium consumption in Australian renal patients.

OBJECTIVE: The study objective was to develop and evaluate the feasibility and validity of a self-administered Scored Sodium Questionnaire (SSQ) for use in the routine clinical care of Australian chronic kidney disease (CKD) patients. DESIGN AND METHODS: The study took place in community-based outreach clinics using a multidisciplinary model of care. Assessment of sources of dietary sodium intake in the target population used comprehensive diet history interviews (Phase 1) to inform development of a 10-item food frequency questionnaire that was scored and validated using 24-hour urinary sodium and 2 alternative dietary intake methods (Phase 2). Subjects were adults with CKD Stages 3 to 5 (Phase 1 n = 30; Phase 2 n = 47). INTERVENTION: On a single day, participants (n = 47) completed the SSQ, feasibility survey, 24-hour urine collection, and 24-hour food record. A diet history interview was also conducted to confirm sodium intake on the day of data collection reflected habitual intake. MAIN OUTCOME MEASURE: Validity of the SSQ score was confirmed by correlation with 24-hour urine sodium. Validity of a cutpoint on the SSQ score to correctly identify high- versus low-sodium consumers was confirmed by receiver operating characteristic curve analysis: area under the curve, sensitivity, and specificity. RESULTS: Total SSQ score correlated significantly with 24-hour urine sodium (r = 0.371; P = .031). Correlation between 24-hour food record and diet history sodium confirmed consumption on the data collection day reflected habitual intake (r = 0.701; P ≤ .001). A cutpoint of 65 or greater on the SSQ score was confirmed as valid to identify high-sodium consumers: area under the curve 0.713, sensitivity 61%, and specificity 82%. CONCLUSION: The SSQ is feasible and valid to assess habitual sodium intake in the Australian CKD population and to identify high-sodium consumers for referral to individualized counseling on a low-sodium diet.

Attitudes, perceptions, and preferences towards SARS CoV-2 testing and vaccination among African American and Hispanic public housing residents, New York City: 2020-2021.

BACKGROUND: African American and Hispanic populations have been affected disproportionately by COVID-19. Reasons are multifactorial and include social and structural determinants of health. During the onset and height of the pandemic, evidence suggested decreased access to SARS CoV-2 testing. In 2020, the National Institutes of Health launched the Rapid Acceleration of Diagnostics (RADx)- Underserved Populations initiative to improve SARS CoV-2 testing in underserved communities. In this study, we explored attitudes, experiences, and barriers to SARS CoV-2 testing and vaccination among New York City public housing residents. METHODS: Between December 2020 and March 2021, we conducted 9 virtual focus groups among 36 low-income minority residents living in New York City public housing. RESULTS: Among residents reporting a prior SARS CoV-2 test, main reasons for testing were to prepare for a medical procedure or because of a high-risk exposure. Barriers to testing included fear of discomfort from the nasal swab, fear of exposure to COVID-19 while traveling to get tested, concerns about the consequences of testing positive and the belief that testing was not necessary. Residents reported a mistrust of information sources and the health care system in general; they depended more on "word of mouth" for information. The major barrier to vaccination was lack of trust in vaccine safety. Residents endorsed more convenient testing, onsite testing at residential buildings, and home self-test kits. Residents also emphasized the need for language-concordant information sharing and for information to come from "people who look like [them] and come from the same background as [them]". CONCLUSIONS: Barriers to SARS CoV-2 testing and vaccination centered on themes of a lack of accurate information, fear, mistrust, safety, and convenience. Resident-endorsed strategies to increase testing include making testing easier to access either through home or onsite testing locations. Education and information sharing by trusted members of the community are important tools to combat misinformation and build trust.

Expanding Per- and Polyfluoroalkyl Substances Coverage in Nontargeted Analysis Using Data-Independent Analysis and IonDecon.

Per- and polyfluoroalkyl substances (PFAS) are widespread, persistent environmental contaminants that have been linked to various health issues. Comprehensive PFAS analysis often relies on ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry (UHPLC HRMS) and molecular fragmentation (MS/MS). However, the selection and fragmentation of ions for MS/MS analysis using data-dependent analysis results in only the topmost abundant ions being selected. To overcome these limitations, All Ions fragmentation (AIF) can be used alongside data-dependent analysis. In AIF, ions across the entire m/z range are simultaneously fragmented; hence, precursor-fragment relationships are lost, leading to a high false positive rate. We introduce IonDecon, which filters All Ions data to only those fragments correlating with precursor ions. This software can be used to deconvolute any All Ions files and generates an open source DDA formatted file, which can be used in any downstream nontargeted analysis workflow. In a neat solution, annotation of PFAS standards using IonDecon and All Ions had the exact same false positive rate as when using DDA; this suggests accurate annotation using All Ions and IonDecon. Furthermore, deconvoluted All Ions spectra retained the most abundant peaks also observed in DDA, while filtering out much of the artifact peaks. In complex samples, incorporating AIF and IonDecon into workflows can enhance the MS/MS coverage of PFAS (more than tripling the number of annotations in domestic sewage). Deconvolution in complex samples of All Ions data using IonDecon did retain some false fragments (fragments not observed when using ion selection, which were not isotopes or multimers), and therefore DDA and intelligent acquisition methods should still be acquired when possible alongside All Ions to decrease the false positive rate. Increased coverage of PFAS can inform on the development of regulations to address the entire PFAS problem, including both legacy and newly discovered PFAS.

The Care Coordination Process: an opportunity to evaluate the impact of structural reform.

Nil.

Developing a national primary care research network: a qualitative study of stakeholder views.

Introduction Primary care research is critical to address Aotearoa New Zealand's (NZ) health sector challenges. These include health inequities, workforce issues and the need for evaluation of health system changes. Internationally, primary care data are routinely collected and used to understand these issues by primary care research and surveillance networks (PCRN). NZ currently has no such infrastructure. Aim To explore health sector stakeholders' views on the utility of, and critical elements needed for, a national PCRN in NZ. Methods Twenty semi-structured interviews and a focus group were conducted with key stakeholders, representing different perspectives within the health sector, including Hauora Maori providers. Data were analysed thematically. Results Six themes were identified that included both challenges within current primary care research and ideas for a future network. The themes were: disconnection between research, practice and policy; desire for better infrastructure; improving health equity for Maori and other groups who experience inequity; responding to the research needs of communities; reciprocity between research and practice; and the need for data to allow evidence-informed decision-making. Improving health equity for Maori was identified as a critical function for a national PCRN. Discussion Stakeholders identified challenges in conducting primary care research and translating research into practice and policy in NZ. Stakeholders from across the health sector supported a national PCRN and identified what its function should be and how it could operate. These views were used to develop a set of recommendations to guide the development of a national PCRN.

Feasibility of low-cost particle sensor types in long-term indoor air pollution health studies after repeated calibration, 2019-2021.

Previous studies have explored using calibrated low-cost particulate matter (PM) sensors, but important research gaps remain regarding long-term performance and reliability. Evaluate longitudinal performance of low-cost particle sensors by measuring sensor performance changes over 2 years of use. 51 low-cost particle sensors (Airbeam 1 N = 29; Airbeam 2 N = 22) were calibrated four times over a 2-year timeframe between 2019 and 2021. Cigarette smoke-specific calibration curves for Airbeam 1 and 2 PM sensors were created by directly comparing simultaneous 1-min readings of a Thermo Scientific Personal DataRAM PDR-1500 unit with a 2.5 µm inlet. Inter-sensor variability in calibration coefficient was high, particularly in Airbeam 1 sensors at study initiation. Calibration coefficients for both sensor types trended downwards over time to < 1 at final calibration timepoint [Airbeam 1 Mean (SD) = 0.87 (0.20); Airbeam 2 Mean (SD) = 0.96 (0.27)]. We lost more Airbeam 1 sensors (N = 27 out of 56, failure rate 48.2%) than Airbeam 2 (N = 2 out of 24, failure rate 8.3%) due to electronics, battery, or data output issues. Evidence suggests degradation over time might depend more on particle sensor type, rather than individual usage. Repeated calibrations of low-cost particle sensors may increase confidence in reported PM levels in longitudinal indoor air pollution studies.