Systemic analysis of lipid metabolism from individuals to multi-organism systems.

Lipid metabolism is recognised as being central to growth, disease and health. Lipids, therefore, have an important place in current research on globally significant topics such as food security and biodiversity loss. However, answering questions in these important fields of research requires not only identification and measurement of lipids in a wider variety of sample types than ever before, but also hypothesis-driven analysis of the resulting 'big data'. We present a novel pipeline that can collect data from a wide range of biological sample types, taking 1 000 000 lipid measurements per 384 well plate, and analyse the data systemically. We provide evidence of the power of the tool through proof-of-principle studies using edible fish (mackerel, bream, seabass) and colonies of Bombus terrestris. Bee colonies were found to be more like mini-ecosystems and there was evidence for considerable changes in lipid metabolism in bees through key developmental stages. This is the first report of either high throughput LCMS lipidomics or systemic analysis in individuals, colonies and ecosystems. This novel approach provides new opportunities to analyse metabolic systems at different scales at a level of detail not previously feasible, to answer research questions about societally important topics.

Adding "Unlikely" as a Clinical Qualifier Is Unlikely to Be of Help: A Retrospective, Single-Center, Cross-Sectional Cohort Study.

ABSTRACT: Clinical correlation is essential to accurate and efficient diagnosis and differential diagnosis in dermatopathology. Poor-quality clinical information can lead to failures and delays in patient care. Some clinicians use the term "unlikely" when submitting a specimen. How frequently the "unlikely" clinical diagnosis correlates with the final pathologic diagnosis is unknown. We studied 203 dermatopathology reports from December 8, 2020, to July 1, 2021, that included the qualifier "unlikely" on the requisition sheet. Samples were stratified into either an inflammatory or neoplastic cohort based on final histopathologic diagnosis, with the neoplastic cohort being further stratified into pigmented and nonpigmented cohorts. Statistical analyses were conducted. The "unlikely" diagnosis in the clinical differential diagnosis and the final histologic diagnosis were the same in 7.9% of the 203 samples studied. This occurred in 8.5% of the inflammatory cohort and 7.6% of the neoplastic cohort. We concluded that the use of the qualifier "unlikely" is not helpful. We acknowledge the limitations of our study because of a small sample.

Synthesis, characterization, and stability assessment of sodium and barium heptamolybdates.

The study of complex phases in nuclear fuels is necessary to understand the physicochemical properties of the fuel. Na6Mo7O24⋅14H2O (1) was prepared via a simplified method and the crystal structure was improved. Upon thermal degradation, 1 decomposes into Na2Mo2O7 and MoO3. Additionally, novel Ba3Mo7O24⋅12H2O (2) was isolated via an aqueous synthetic route and characterized via FTIR and elemental analysis. PXRD pattern of 2 was determined. Thermal degradation of 2 indicates formation of BaMoO4, BaMo3O10, MoO3, and an unidentified phase.

Gaining Recovery in Addiction for Community Elders (GRACE) Project: The Impact of Age-Specific Care on Clinical Outcomes and Health Care Resource Utilization in Older Adults With Substance Use Disorder in an Interprofessional Addiction Clinic.

BACKGROUND: The prevalence of substance use disorders (SUDs) in older adults has been increasing, necessitating tailored and effective addiction care for this aging demographic. AIMS: The purpose of this study was to assess the impact of age-specific, interprofessional addiction care on clinical outcomes and health care resource utilization in older adults with SUD. METHODS: This quasi-experimental study directly compares patients enrolled in the Gaining Recovery in Addiction for Community Elders (GRACE) Project, an interprofessional age-specific addictions treatment program, with age-matched older adults who received conventional "treatment as usual" (TAU). Through retrospective comparative analysis, substance use outcomes, mental and physical health improvements, and inappropriate use of emergency services were examined among 78 older adults with SUD. RESULTS: Clinical outcomes and health care resource utilization were superior for older adults who received age-specific addictions care through the GRACE Project, as compared to mixed-age conventional "TAU." GRACE patients had improved treatment adherence, fewer relapses, and longer treatment engagement. While both groups exhibited significant reductions in depression and anxiety scores, GRACE patients showed greater improvements. This group demonstrated superior control of both hypertension and diabetes. Importantly, they had fewer inappropriate emergency department visits and avoidable hospitalizations than conventional "TAU." CONCLUSIONS: Addiction treatment delivered by an interprofessional team to meet the unique strengths and needs of older adults has the potential to improve treatment adherence and more favorable long-term outcomes in substance use, mental health, and chronic medical conditions. Nurses are poised to lead interprofessional teams to meet the growing demand for specialized addiction treatment and integrated care for older adults.

The prescription and monitoring of conventional synthetic disease-modifying anti-rheumatic drugs: British Society for Rheumatology guideline scope.

This guideline will provide up-to-date, evidence-based recommendations on the safe use of non-biologic DMARDs, also called conventional synthetic DMARDs (csDMARD), across the full spectrum of autoimmune rheumatic diseases. The guideline will update the guideline published in 2017 and will be expanded to include people of all ages. Updated information on the monitoring of DMARDs and vaccinations will be included. The guideline will be developed using the methods and processes described in the British Society for Rheumatology's 'Creating clinical guidelines: our protocol', updated 2023.

Motivators, Barriers, and Facilitators to Choosing Care in VA Facilities Versus VA-Purchased Care.

Many Veterans receive Department of Veterans Affairs (VA)-purchased care from non-VA facilities but little is known about factors that Veterans consider for this choice. Between May 2020 and August 2021, we surveyed VA-purchased care-eligible VA patients about barriers and facilitators to choosing where to receive care. We examined the association between travel time to their VA facility and their choice of VA-purchased care (VA-paid health care received in non-VA settings) versus VA facility and whether this association was modified by distrust. We received 1,662 responses and 692 (42%) chose a VA facility. Eighty percent reported quality care was in their top three factors that influenced their decision. Respondents with the highest distrust and who lived >1 hr from the nearest VA facility had the lowest predicted probability (PP) of choosing VA (PP 15%; 95% confidence interval: 10%-20%). Veterans value quality of care. VA and other health care systems should consider patient-centered ways to improve and publicize quality and reduce distrust.

Advancing PFAS characterization: Development and optimization of a UV-H2O2-TOP assay for improved PFCA chain length preservation and organic matter tolerance.

As per- and polyfluoroalkyl substances (PFAS) infiltrate the environment via industrial, commercial, and domestic sources, the demand for robust, cost-effective, and straightforward analytical assays intensifies to enhance PFAS characterization and quantification. To address this demand, this study introduces a novel UV-H2O2-TOP assay, identifying optimal parameters such as pH (5-9), oxidant concentration (500 mM H2O2), activation rate (63 mM H2O2 h-1), and an acceptable total organic carbon (TOC) limit (~1000 mg/L TOC) to achieve maximum PFAA precursor conversion. Additional work was performed further optimizing the UV-TOP assay, by confirming its superiority to heat activation, identifying the effectiveness of different persulfate salts, and investigating different concentrations of sodium persulfate and sodium hydroxide at a 1:2.5 ratio on PFCA yield. Our investigation concluded by applying the UV-H2O2-TOP assay, using sodium persulfate as the TOP assay oxidant, to 6:2 FTS and five different AFFF samples. High-resolution mass spectrometry and an expanded analytical suite support sample analysis, facilitating direct quantification of ultra-short chain perfluoroalkyl carboxylates (PFCAs) and common fluorotelomer compounds including 5:3/5:1:2 fluorotelomer betaine and 6:2 fluorotelomer sulfonamido betaine. Results highlight several advantages of this tandem UV-activated method, including enhanced preservation of perfluoroalkyl chains (post-oxidation of 6:2 fluorotelomer sulfonate resulted in 28 % PFHpA, 47 % PFHxA, 25 % C3-C5 PFCA), capacity to handle high TOC limits (1000 mg/L TOC), and ability to incorporate higher persulfate concentrations in a single oxidation cycle.

Effect of Immunosuppression on the Immune Response to SARS-CoV-2 Infection and Vaccination.

Immunosuppressive treatment in patients with rheumatic diseases can maintain disease remission but also increase risk of infection. Their response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination is frequently blunted. In this study we evaluated the effect of immunosuppression exposure on humoral and T cell immune responses to SARS-CoV-2 infection and vaccination in two distinct cohorts of patients; one during acute SARS-CoV-2 infection and 3 months later during convalescence, and another prior to SARS-CoV-2 vaccination, with follow up sampling 6 weeks after vaccination. Results were compared between rituximab-exposed (in previous 6 months), immunosuppression-exposed (in previous 3 months), and non-immunosuppressed groups. The immune cell phenotype was defined by flow cytometry and ELISA. Antigen specific T cell responses were estimated using a whole blood stimulation interferon-γ release assay. A focused post-vaccine assessment of rituximab-treated patients using high dimensional spectral cytometry was conducted. Acute SARS-CoV-2 infection was characterised by T cell lymphopenia, and a reduction in NK cells and naïve CD4 and CD8 cells, without any significant differences between immunosuppressed and non-immunosuppressed patient groups. Conversely, activated CD4 and CD8 cell counts increased in non-immunosuppressed patients with acute SARS-CoV-2 infection but this response was blunted in the presence of immunosuppression. In rituximab-treated patients, antigen-specific T cell responses were preserved in SARS-CoV-2 vaccination, but patients were unable to mount an appropriate humoral response.

Growth of Community Outpatient Care in the Veterans Affairs System After the MISSION Act.

BACKGROUND: The Maintaining Internal Systems and Strengthening Integrated Outside Networks (MISSION) Act of 2018 authorized a major expansion of purchased care in the community for Veterans experiencing access barriers in the Veterans Affairs (VA) health care system. OBJECTIVE: To estimate changes in primary care, mental health, and emergency/urgent care visits in the VA and community fiscal years (FY) 2018-2021 and differences between rural and urban clinics. DESIGN: A national, longitudinal study of VA clinics and outpatient utilization. Clinic-level analysis was conducted to estimate changes in number and proportion of clinic visits provided in the community associated with the MISSION Act adjusting for clinic characteristics and underlying time trends. PARTICIPANTS: In total, 1050 VA clinics and 6.6 million Veterans assigned to primary care. MAIN MEASURES: Number of primary care, mental health, and emergency/urgent care visits provided in the VA and community and the proportion provided in the community. KEY RESULTS: Nationally, community primary care visits increased by 107% (50,611 to 104,923), community mental health visits increased by 167% (100,701 to 268,976), and community emergency/urgent care visits increased by 129% (142,262 to 325,407) from the first quarter of 2018 to last quarter of 2021. In adjusted analysis, after MISSION Act implementation, there was an increase in community visits as a proportion of total clinic visits for emergency/urgent care and mental health but not primary care. Rural clinics had larger increases in the proportion of community visits for primary care and emergency/urgent care than urban clinics. CONCLUSIONS: After the MISSION Act, more outpatient care shifted to the community for emergency/urgent care and mental health care but not primary care. Community care utilization increased more in rural compared to urban clinics for primary care and emergency/urgent care. These findings highlight the challenges and importance of maintaining provider networks in rural areas to ensure access to care.

Computable phenotype for real-world, data-driven retrospective identification of relapse in ANCA-associated vasculitis.

OBJECTIVE: ANCA-associated vasculitis (AAV) is a relapsing-remitting disease, resulting in incremental tissue injury. The gold-standard relapse definition (Birmingham Vasculitis Activity Score, BVAS>0) is often missing or inaccurate in registry settings, leading to errors in ascertainment of this key outcome. We sought to create a computable phenotype (CP) to automate retrospective identification of relapse using real-world data in the research setting. METHODS: We studied 536 patients with AAV and >6 months follow-up recruited to the Rare Kidney Disease registry (a national longitudinal, multicentre cohort study). We followed five steps: (1) independent encounter adjudication using primary medical records to assign the ground truth, (2) selection of data elements (DEs), (3) CP development using multilevel regression modelling, (4) internal validation and (5) development of additional models to handle missingness. Cut-points were determined by maximising the F1-score. We developed a web application for CP implementation, which outputs an individualised probability of relapse. RESULTS: Development and validation datasets comprised 1209 and 377 encounters, respectively. After classifying encounters with diagnostic histopathology as relapse, we identified five key DEs; DE1: change in ANCA level, DE2: suggestive blood/urine tests, DE3: suggestive imaging, DE4: immunosuppression status, DE5: immunosuppression change. F1-score, sensitivity and specificity were 0.85 (95% CI 0.77 to 0.92), 0.89 (95% CI 0.80 to 0.99) and 0.96 (95% CI 0.93 to 0.99), respectively. Where DE5 was missing, DE2 plus either DE1/DE3 were required to match the accuracy of BVAS. CONCLUSIONS: This CP accurately quantifies the individualised probability of relapse in AAV retrospectively, using objective, readily accessible registry data. This framework could be leveraged for other outcomes and relapsing diseases.

Pediatric Acne Vulgaris: A Guide for Recognition, Examination, Referral, and Treatment.

Acne is a common skin condition in adolescent patients but much less common in childhood. Pediatric providers should be familiar with the varying presentations in the pediatric population and recognize when additional physical signs of hyperandrogenism are present. This article details the pathogenesis and presentation of acne in infancy, mid-childhood, and preadolescence. The differential diagnosis is discussed and recommendations for initial workup, referral, and treatment are provided. [Pediatr Ann. 2024;53(4):e115-e120.].

The Clinical Resource Hub Telehealth Program and Use of Primary Care, Emergency, and Inpatient Care During the COVID-19 Pandemic.

BACKGROUND: The COVID-19 pandemic disrupted delivery of health care services worldwide. We examined the impact of the pandemic on clinics participating in the Veterans Affairs (VA) Clinical Resource Hub (CRH) program, rolled out nationally in October 2019, to improve access to care at under-resourced VA clinics or "spoke" sites through telehealth services delivered by regional "hub" sites. OBJECTIVE: To assess whether the CRH program was associated with increased access to primary care, we compared use of primary, emergency, and inpatient care at sites that adopted CRH for primary care (CRH-PC) with sites that did not adopt CRH-PC, pre-post pandemic onset. DESIGN: Difference-in-difference and event study analyses, adjusting for site characteristics. STUDY COHORT: A total of 1050 sites (254 CRH-PC sites; 796 comparison sites), fiscal years (FY) 2019-2021. INTERVENTION: CRH Program for Primary Care. MAIN MEASURES: Quarterly number of VA visits per site for primary care (across all and by modality, in-person, video, and phone), emergency care, and inpatient care. RESULTS: In adjusted analyses, CRH-PC sites, compared with non-CRH-PC sites, had on average 221 additional primary care visits (a volume increase of 3.4% compared to pre-pandemic). By modality, CRH-PC sites had 643 fewer in-person visits post-pandemic (- 14.4%) but 723 and 128 more phone and video visits (+ 39.9% and + 159.5%), respectively. CRH-PC sites, compared with non-CRH-PC sites, had fewer VA ED visits (- 4.2%) and hospital stays (- 5.1%) in VA medical centers. Examining visits per patient, we found that CRH-PC sites had 48 additional telephone primary care visits per 1000 primary care patients (an increase of 9.8%), compared to non-program sites. CONCLUSIONS: VA's pre-pandemic rollout of a new primary care telehealth program intended to improve access facilitated primary care visits during the pandemic, a period fraught with care disruptions, and limited in-person health care delivery, indicating the potential for the program to offer health system resilience.

Data quality and patient characteristics in European ANCA-associated vasculitis registries: data retrieval by federated querying.

OBJECTIVES: This study aims to describe the data structure and harmonisation process, explore data quality and define characteristics, treatment, and outcomes of patients across six federated antineutrophil cytoplasmic antibody-associated vasculitis (AAV) registries. METHODS: Through creation of the vasculitis-specific Findable, Accessible, Interoperable, Reusable, VASCulitis ontology, we harmonised the registries and enabled semantic interoperability. We assessed data quality across the domains of uniqueness, consistency, completeness and correctness. Aggregated data were retrieved using the semantic query language SPARQL Protocol and Resource Description Framework Query Language (SPARQL) and outcome rates were assessed through random effects meta-analysis. RESULTS: A total of 5282 cases of AAV were identified. Uniqueness and data-type consistency were 100% across all assessed variables. Completeness and correctness varied from 49%-100% to 60%-100%, respectively. There were 2754 (52.1%) cases classified as granulomatosis with polyangiitis (GPA), 1580 (29.9%) as microscopic polyangiitis and 937 (17.7%) as eosinophilic GPA. The pattern of organ involvement included: lung in 3281 (65.1%), ear-nose-throat in 2860 (56.7%) and kidney in 2534 (50.2%). Intravenous cyclophosphamide was used as remission induction therapy in 982 (50.7%), rituximab in 505 (17.7%) and pulsed intravenous glucocorticoid use was highly variable (11%-91%). Overall mortality and incidence rates of end-stage kidney disease were 28.8 (95% CI 19.7 to 42.2) and 24.8 (95% CI 19.7 to 31.1) per 1000 patient-years, respectively. CONCLUSIONS: In the largest reported AAV cohort-study, we federated patient registries using semantic web technologies and highlighted concerns about data quality. The comparison of patient characteristics, treatment and outcomes was hampered by heterogeneous recruitment settings.

The Improved Kidney Risk Score in ANCA-Associated Vasculitis for Clinical Practice and Trials.

SIGNIFICANCE STATEMENT: Reliable prediction tools are needed to personalize treatment in ANCA-associated GN. More than 1500 patients were collated in an international longitudinal study to revise the ANCA kidney risk score. The score showed satisfactory performance, mimicking the original study (Harrell's C=0.779). In the development cohort of 959 patients, no additional parameters aiding the tool were detected, but replacing the GFR with creatinine identified an additional cutoff. The parameter interstitial fibrosis and tubular atrophy was modified to allow wider access, risk points were reweighted, and a fourth risk group was created, improving predictive ability (C=0.831). In the validation, the new model performed similarly well with excellent calibration and discrimination ( n =480, C=0.821). The revised score optimizes prognostication for clinical practice and trials. BACKGROUND: Reliable prediction tools are needed to personalize treatment in ANCA-associated GN. A retrospective international longitudinal cohort was collated to revise the ANCA renal risk score. METHODS: The primary end point was ESKD with patients censored at last follow-up. Cox proportional hazards were used to reweight risk factors. Kaplan-Meier curves, Harrell's C statistic, receiver operating characteristics, and calibration plots were used to assess model performance. RESULTS: Of 1591 patients, 1439 were included in the final analyses, 2:1 randomly allocated per center to development and validation cohorts (52% male, median age 64 years). In the development cohort ( n =959), the ANCA renal risk score was validated and calibrated, and parameters were reinvestigated modifying interstitial fibrosis and tubular atrophy allowing semiquantitative reporting. An additional cutoff for kidney function (K) was identified, and serum creatinine replaced GFR (K0: <250 µ mol/L=0, K1: 250-450 µ mol/L=4, K2: >450 µ mol/L=11 points). The risk points for the percentage of normal glomeruli (N) and interstitial fibrosis and tubular atrophy (T) were reweighted (N0: >25%=0, N1: 10%-25%=4, N2: <10%=7, T0: none/mild or <25%=0, T1: ≥ mild-moderate or ≥25%=3 points), and four risk groups created: low (0-4 points), moderate (5-11), high (12-18), and very high (21). Discrimination was C=0.831, and the 3-year kidney survival was 96%, 79%, 54%, and 19%, respectively. The revised score performed similarly well in the validation cohort with excellent calibration and discrimination ( n =480, C=0.821). CONCLUSIONS: The updated score optimizes clinicopathologic prognostication for clinical practice and trials.

Improving detection of cystic fibrosis related liver disease using liver fibrosis assessment tools.

Background & aims: Cystic Fibrosis related liver disease (CFLD) is the 3rd largest cause of death in Cystic Fibrosis (CF). As advances in pulmonary therapies have increased life-expectancy, CFLD has become more prevalent. Current guidelines may underdiagnose liver fibrosis, particularly in its early stages. Newer modalities for the assessment of fibrosis may provide a more accurate assessment. FibroScan is validated in assessing fibrosis for several aetiologies including alcohol and fatty liver, the CFLD cohort have an entirely different phenotype so the cut off values are not transferrable. We appraised fibrosis assessment tools to improve diagnosis of CFLD. Methods: A prospective cohort (n = 114) of patients from the Manchester Adult Cystic Fibrosis Centre, UK were identified at annual assessment. Demographic data including co-morbidity, CFTR genotyping, biochemistry and imaging were used alongside current guidelines to group into CFLD and CF without evidence of liver disease. All patients underwent liver stiffness measurement (LSM) and assessment of serum-based fibrosis biomarker panels. A new diagnostic criterion was created and validated in a second, independent cohort. Results: 12 of 114 patient classified as CFLD according to the European Cystic Fibrosis Society best practice guidelines. No specific risk factors for development of CFLD were identified. Liver enzymes were elevated in patients with CFLD. Serum biomarker panels did not improve diagnostic criteria. LSM accurately predicted CFLD. A new diagnostic criterion was proposed and validated in a separate cohort, accurately predicating CFLD in 10 of 32 patients (31 %). Conclusion: We present a cohort of patients with CF assessed for the presence of liver fibrosis using blood biomarkers and LSM based platforms. We propose a new, simplified diagnostic criteria, capable of accurately predicting liver disease in patients with CF.Clinical trials number: NCT04277819.

Mouthparts of the bumblebee (Bombus terrestris) exhibit poor acuity for the detection of pesticides in nectar.

Bees are important pollinators of agricultural crops, but their populations are at risk when pesticides are used. One of the largest risks bees face is poisoning of floral nectar and pollen by insecticides. Studies of bee detection of neonicotinoids have reported contradictory evidence about whether bees can taste these pesticides in sucrose solutions and hence avoid them. Here, we use an assay for the detection of food aversion combined with single-sensillum electrophysiology to test whether the mouthparts of the buff-tailed bumblebee (Bombus terrestris) detect the presence of pesticides in a solution that mimicked the nectar of oilseed rape (Brassica napus). Bees did not avoid consuming solutions containing concentrations of imidacloprid, thiamethoxam, clothianidin, or sulfoxaflor spanning six orders of magnitude, even when these solutions contained lethal doses. Only extremely high concentrations of the pesticides altered spiking in gustatory neurons through a slight reduction in firing rate or change in the rate of adaptation. These data provide strong evidence that bumblebees cannot detect or avoid field-relevant concentrations of pesticides using information from their mouthparts. As bees rarely contact floral nectar with other body parts, we predict that they are at high risk of unwittingly consuming pesticides in the nectar of pesticide-treated crops.

Bees and other pollinators often encounter pesticides while collecting nectar and pollen from agricultural crops. Widely used to protect crops, pesticides are toxic to insects and have contributed to population declines in all bee species. One way that bees might be able to avoid pesticides is using their incredibly good sense of taste, which can detect subtle differences between sugary solutions. Therefore, if pesticides taste bitter to them, bumblebees may be able to avoid feeding treated crops. However, it was not clear if bees can taste pesticides. Previous studies investigating whether they can taste a group of pesticides called "neonicotinoids" gave contradictory results. Furthermore, explicit behavioural tests of their ability to taste pesticides had not been performed. To shed light on this, Parkinson et al. compared the responses of neurons within structures used for detecting taste in bumblees eating a pure sugar solution with those eating a solution containing pesticides. Experiments with a group of pesticides known as 'cholinergic' showed that neuron responses were the same whether the sugar solution contained pesticides or not. Secondly, by looking at bumblebee feeding behaviour, Parkinson et al. found that bees offered both pure and pesticide-laced sugar solutions would still drink the pesticide solution, even when it was toxic enough to make them very ill or kill them. This was the case regardless of which pesticide was used. The experiments showed that bumblebees cannot use their sense of taste to avoid drinking pesticide-laced nectar, which is an important finding for policymakers making decisions about the use of pesticides on agricultural crops. It is possible that bees simply have a poor sense of bitter taste. However, in the future, these methods could be used to identify a compound that tastes bad to bees. Including such a compound in pesticides, could deter bees from feeding on pesticide-treated crops that do not require pollination, and help to restore their declining populations.

Human equivalent doses of L-DOPA rescues retinal morphology and visual function in a murine model of albinism.

L-DOPA is deficient in the developing albino eye, resulting in abnormalities of retinal development and visual impairment. Ongoing retinal development after birth has also been demonstrated in the developing albino eye offering a potential therapeutic window in humans. To study whether human equivalent doses of L-DOPA/Carbidopa administered during the crucial postnatal period of neuroplasticity can rescue visual function, OCA C57BL/6 J-c2J OCA1 mice were treated with a 28-day course of oral L-DOPA/Carbidopa at 3 different doses from 15 to 43 days postnatal age (PNA) and for 3 different lengths of treatment, to identify optimum dosage and treatment length. Visual electrophysiology, acuity, and retinal morphology were measured at 4, 5, 6, 12 and 16 weeks PNA and compared to untreated C57BL/6 J (WT) and OCA1 mice. Quantification of PEDF, ßIII-tubulin and syntaxin-3 expression was also performed. Our data showed impaired retinal morphology, decreased retinal function and lower visual acuity in untreated OCA1 mice compared to WT mice. These changes were diminished or eliminated when treated with higher doses of L-DOPA/Carbidopa. Our results demonstrate that oral L-DOPA/Carbidopa supplementation at human equivalent doses during the postnatal critical period of retinal neuroplasticity can rescue visual retinal morphology and retinal function, via PEDF upregulation and modulation of retinal synaptogenesis, providing a further step towards developing an effective treatment for albinism patients.

Effects of elexacaftor/tezacaftor/ivacaftor on liver fibrosis markers in adults with cystic fibrosis.

BACKGROUND: There are limited studies to date on the effects of elexacaftor/tezacaftor/ivacaftor (E/T/I) on markers of liver fibrosis in adults with cystic fibrosis (CF). This study aims to analyse changes in makers of liver fibrosis before and after initiation of E/T/I in CF adults. METHODS: Outcome measures of liver fibrosis, including liver stiffness measurement (LSM) using FibroScan, AST-to-platelet-ratio index (APRI) and gamma-GT-to-platelet-ratio (GPR) were available in 74 CF adults following initiation of E/T/I. This was compared to historical data collected in 2018 prior to UK availability of E/T/I. RESULTS: The median duration of E/T/I therapy at the time liver fibrosis markers were repeated was 21 (IQR: 17-25) months. There was an increase in APRI from historical measurement to follow-up but no change in LSM or GPR. There were no differences in change in fibrosis markers according to CF liver disease (CFLD) status, although those with a raised LSM at baseline (>6.8 kPa) (n = 14) had a significant reduction in LSM from historical measurement to follow-up versus those with a normal historical value (-3.3 kPa vs 0.25 kPa, p < 0.01). CONCLUSIONS: Apart from APRI, we found no changes in liver fibrosis outcomes after initiation of E/T/I in adults with CF. Those with a historical diagnosis of CFLD had no significant worsening or improvement of liver fibrosis markers. We did observe a reduction in LSM in those with liver nodularity, with an initial highest result suggesting a potential positive treatment effect of E/T/I in this category of those with severe CFLD.

Instant Detection of Synthetic Cannabinoids on Physical Matrices, Implemented on a Low-Cost, Ultraportable Device.

Synthetic cannabinoids (SCs) make up a class of novel psychoactive substances (NPS), used predominantly in prisons and homeless communities in the U.K. SCs can have severe side effects, including psychosis, stroke, and seizures, with numerous reported deaths associated with their use. The chemical diversity of SCs presents the major challenge to their detection since approaches relying on specific molecular recognition become outdated almost immediately. Ideally one would have a generic approach to detecting SCs in portable settings. The problem of SC detection is more challenging still because the majority of SCs enter the prison estate adsorbed onto physical matrices such as paper, fabric, or herb materials. That is, regardless of the detection modality used, the necessary extraction step reduces the effectiveness and ability to rapidly screen materials on-site. Herein, we demonstrate a truly instant generic test for SCs, tested against real-world drug seizures. The test is based on two advances. First, we identify a spectrally silent region in the emission spectrum of most physical matrices. Second, the finding that background signals (including from autofluorescence) can be accurately predicted is based on tracking the fraction of absorbed light from the irradiation source. Finally, we demonstrate that the intrinsic fluorescence of a large range of physical substrates can be leveraged to track the presence of other drugs of interest, including the most recent iterations of benzodiazepines and opioids. We demonstrate the implementation of our presumptive test in a portable, pocket-sized device that will find immediate utility in prisons and law enforcement agencies around the world.