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Leila Katabi,1 Erica Stevens,1 Mona Ascha,2 Kavita Arora3,4 1Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA; 2Division of Plastic and Reconstructive Surgery, Department of Surgery, University Hospitals Cleveland Medical Center, Cleveland, OH, 44106, USA; 3Department of Obstetrics and Gynecology, MetroHealth Medical Center, Cleveland, OH, 44109, USA; 4Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill, NC, 27514, USACorrespondence: Kavita Arora, Department of Obstetrics and Gynecology, University of North Carolina, 101 Manning Drive, Chapel Hill, NC, 27514, USA, Tel +1 919-843-8295, Email kavita.shah.arora@gmail.comPurpose: Etonogestrel subdermal implants are a commonly used contraceptive device placed in the medial upper arm. Plastic and orthopedic surgeons may be consulted for difficult implant removals. We performed a case–control study comparing patients undergoing surgical and uncomplicated in-office removal at our institution.Patients and Methods: We identified patients who underwent operative removal of implantable contraceptive devices by plastic or orthopedic surgeons at our institution from January 2014 to October 2019. Patients who underwent uncomplicated office removal during the same time were compared. Demographic and surgical variables were collected, and descriptive statistics were calculated. Univariate and multivariate logistic regression was performed with surgical versus outpatient removal as the outcome of interest.Results: A total of 669 patients undergoing etonogestrel subdermal implant removals were identified during the five-year study period, of which thirteen patients required surgical removal (1.9%) and 326 were selected as uncomplicated removal comparisons. There were no significant differences in median (IQR) body mass index (BMI) (31.1 [28.2, 35.2] versus 29.3 [24.0, 35.1], p = 0.19), median (IQR) weight gain since device placement (5 [− 0.6, 14.7] kilograms versus 1.6 [− 1.2, 5.8] kilograms, p = 0.15), or length of time since device insertion (2.3 [0.8, 2.8] years versus 1.0 [0.4, 2.2] years, p = 0.17). Of those who needed surgical removal, the most common indication for implant removal was device expiration (n = 5, 38.5%). Devices placed by OBGYN attendings were less likely to require surgical removal (p = 0.02). Family medicine attendings were more likely to refer patients for surgical removal (p = 0.02). No significant findings were detected on univariate or multivariate regression. Among surgical removals, radiography was the most frequently used imaging modality. Implants were most frequently subdermal (n = 11, 84.6%) though intramuscular placement was also identified (n = 2, 15.4%). Only one patient had residual paresthesia along the length of the incision. No other complications were identified.Conclusion: We did not identify risk factors associated with the difficult removal of etonogestrel subdermal implants. Practitioners should consult upper extremity surgeons if they encounter difficult removals.Keywords: nexplanon, etonogestrel subdermal implant, upper extremity surgery, implantable contraception

Context. River regulation, coupled with climate change, has caused significant declines in global freshwater biodiversity. In Australia, water extraction within the Murray–Darling Basin (MDB) has reduced the frequency, extent and duration with which floodplains are inundated, resulting in widespread declines in wetland-dependent biodiversity, including reptiles. The endangered Ngabi (Hemiaspis damelii) is associated with floodplain systems in the MDB, yet its distribution and ecological requirements are poorly understood, hampering conservation actions. Aims. We sought to validate an assumption that Ngabi is associated with wetland vegetation communities before investigating factors affecting its probability of detection in the lower Murrumbidgee catchment in southern New South Wales. We predicted Ngabi occurrence patterns would relate to frog abundance, wetland hydrology, microhabitat attributes and meteorological variables. Methods. We compared Ngabi observations from 16 paired wetland and dryland vegetation transects to evaluate associations with vegetation type. We then used generalised linear mixed models to relate snake presence and absence to prey (frog abundance), microhabitat (logs and ground cover), wetland hydrology (water depth and inundation frequency) and meteorological conditions, using 12 repeat surveys between September 2018 and March 2021. Key results. Fiftyeight snakes were observed at five of eight wetlands during the study. Ngabi was exclusively recorded in river red gum/spike rush or lignum vegetation communities, and was absent from sandhill woodland or chenopod communities. The probability of detecting Ngabi increased with ambient temperature and weakly with wetland inundation frequency, but not frog abundance, microhabitat attributes or year. Conclusions. Ngabi is strongly associated with floodplain vegetation communities and, to some extent, frequently inundated wetlands in southern NSW, suggesting water management agencies should incorporate threatened floodplain snake species into future wetland management plans. The use of environmental water to restore aspects of flow regimes, improve wetland health and aquatic diversity is likely to benefit other wetlanddependent snake populations across the MDB. Implications. The positive relationship between Ngabi detections and ambient temperature will be important for designing an effective monitoring program for the species across the MDB. Furthermore, our findings provide insight into the benefits of using environmental water to create wetland refuges to maintain floodplain snake populations during droughts. [ABSTRACT FROM AUTHOR]

Introduction: Chemotherapy toxicity tools are rarely studied in patients with hematologic malignancy (HM). The primary aim of this pilot study was to determine the predictive ability of the Cancer and Aging Research Group (CARG) chemo-toxicity calculator in estimating grade 3-5 toxicity in patients with HM., Materials and Methods: Patients 60 years and older with HM were prospectively evaluated using the CARG chemo-toxicity calculator. Discrimination and calibration were checked by applying the published model in our data. Additionally, a full geriatric assessment (GA), the Short Physical Performance Battery (SPPB), and health related quality of life (HRQoL) were captured longitudinally at the start of treatment and at end of study. Secondary aims explored the association of GA metrics with chemo-related toxicities and survival., Results: One hundred forty-five patients were approached, 118 patients consented, and 97 patients were evaluable. Most patients were newly diagnosed (n = 91). The median CARG score was 9 (range 4-18). The CARG score was not validated in our cohort of older patients with HM, with area under the receiver operation characteristic curve being 0.53 (95 % CI: 0.41-0.65). In multivariable analysis, after controlling for disease type, risk factors associated with grade 3-5 toxicity included living alone (hazard ratio [HR] 4.24, 95 %CI: 2.07-8.68, p < 0.001), increase in body mass index (HR 1.06, 95 %CI: 1.01-1.12, p = 0.03) and a higher social activities score (HR 1.27, 95 %CI: 1.06-1.51, p = 0.01). In multivariable analysis of overall survival, the only prognostic factor was an objective marker of physical function (SPPB score HR = 0.85, 95 %CI:0.78-0.93, p < 0.001)., Discussion: The CARG chemo-toxicity calculator was not predictive of grade 3-5 toxicity in patients with hematologic malignancy. The SPPB was associated with overall survival in multivariable analysis, suggesting future use as an objective biomarker in HM. We also report a comprehensive trajectory of function, QoL, psychosocial well-being, and cognition among older adults with HM. The predictive accuracy of the CARG chemo-toxicity calculator may be affected by the diverse range of HM treatment options that are not traditional chemotherapy., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Older adults with multiple sclerosis (MS) face unique challenges arising from age-related changes in MS pathophysiology and overlapping geriatric syndromes. There is a need for geriatrics-focused multidisciplinary care for the rapidly growing older MS population., Objective: To design and implement a geriatric multidisciplinary clinic for older adults with MS., Methods: We describe the development of a multidisciplinary approach to geriatric MS care within a single institution through the implementation of the Aging with MS Clinic. The clinic model was conceived through collaboration between neurology and geriatric medicine to provide comprehensive care for older adults with MS who are uniquely affected by overlapping symptoms of aging and MS (e.g., frailty, falls, functional decline, multiple comorbidities, polypharmacy, cognitive impairment, nutritional deficits, barriers to access healthcare). Multidisciplinary specialists were recruited to staff the clinic, and initial patient satisfaction outcomes were collected., Results: The team of multidisciplinary specialists staffing the clinic consists of a MS advanced practice practitioner, MS pharmacist, physical therapist, neuropsychologist, dietitian, and social worker. A clinic template was devised where 4 patients with MS over age 60 are seen by each specialist during each half-day clinic session. Initial patient satisfaction surveys from 25 participants showed overwhelmingly positive feedback. A majority of participants (92%) agreed that the clinic was well-organized, while 92% felt they benefitted from attending. Additionally, 80% of participants reported that the clinic improved their overall quality of care., Conclusion: The Aging with MS clinic outlines a model for comprehensive geriatric assessment and care in older adults with MS by a team of multidisciplinary specialists. Initial feedback from patients who attended the clinic conveyed improved quality of care., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest pertinent to this manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The cerebral biomarkers, neurofilament light chain (NfL), amyloid-β, tau, and neuron specific enolase (NSE) reflect a wide spectrum of neurological damage in the brain and spinal cord. With this study, we aimed to assess whether these biomarkers hold any potential diagnostic value for the three most common canine neurological diseases. Canines suffering from meningoencephalitis of unknown origin (MUO), brain tumors, and selected non-infectious myelopathies were included. For each diagnosis, we analyzed these biomarkers in the cerebrospinal fluid collected via cranial puncture from the cisterna magna. Elevated levels of CSF tau, NfL, and NSE were observed in MUO, with all three biomarkers being intercorrelated. Tau and NSE were increased while amyloid-β was decreased in dogs suffering from tumors. In contrast, no biomarker changes were observed in dogs with myelopathies. Covariates such as age, sex, or castration had minimal impact. CSF biomarkers may reflect molecular changes related to MUO and tumors, but not to non-infectious myelopathies. The combination of NfL, tau, and NSE may represent useful biomarkers for MUO as they reflect the same pathology and are not influenced by age., (© 2024. The Author(s).)

Background: The impacts of climate change-related extreme weather events (EWEs) on Medication for Opioid Use Disorders (MOUD) implementation for Medicaid beneficiaries are relatively unknown. Such information is critical to disaster planning and other implementation strategies. In this study we examined implementation determinants and strategies for MOUD during EWEs., Methods: The Louisiana-based Community Resilience Learning Collaborative and Research Network (C-LEARN) utilized Rapid Assessment Procedures-Informed Community Ethnography (RAPICE), involving community leaders in study design, execution, and data analysis. We conducted qualitative semi-structured interviews with 42 individuals, including MOUD Medicaid member patients and their caregivers, healthcare providers and administrators, and public health officials with experience with climate-related disasters. We mapped key themes onto updated Consolidated Framework for Implementation Research domains., Results: MOUD use is limited during EWEs by pharmacy closures, challenges to medication prescription and access across state lines, hospital and clinic service limits, overcrowded emergency departments, and disrupted communications with providers. MOUD demand simultaneously increases due to the stress associated with displacement, resource loss, the COVID-19 pandemic, and social determinants of health. Effective implementation strategies include healthcare system disaster plans with protocols for clear and regular patient-provider communication, community outreach, additional staffing, and virtual delivery of services. Providers can also increase MOUD access by having remote access to EHRs, laptops and contact information, resource lists, collaborative networks, and contact with patients via call centers and social media. Patients can retain access to MOUD via online patient portals, health apps, call centers, and provider calls and texts. The impact of EWEs on MOUD access and use is also influenced by individual characteristics of both patients and providers., Conclusions: The increasing frequency and severity of climate-related EWEs poses a serious threat to MOUD for Medicaid beneficiaries. MOUD-specific disaster planning and use of telehealth for maintaining contact and providing care are effective strategies for MOUD implementation during EWEs. Potential considerations for policies and practices of Medicaid, providers, and others to benefit members during hurricanes or major community stressors, include changes in Medicaid policies to enable access to MOUD by interstate evacuees, improvement of medication refill flexibilities, and incentivization of telehealth services for more systematic use., Competing Interests: Declaration of competing interest The authors of the present manuscript have no conflicts of interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Legacies can become intertwined, none more so than the body of work of Dr. Andrew Sharpley examining agricultural nutrient delivery to waterbodies and the phosphorus (P) accumulation in agricultural soils, or "legacy P." Although Sharpley's work focused on the anthropogenic influence on soil P, our study suggests soils of the Lower Mississippi Alluvial Plain (MAP) represent a natural legacy with moderate levels of available P resulting from minimal anthropogenic input. In 2019, we collected surface (0-5 cm) soil samples from four regionally dominant soil series in either cropland or forested land uses, spanning 76 locations within the MAP. Soil chemical and physical properties were measured utilizing a suite of extractions and texture analysis to correlate properties with soil P values. Total soil P did not vary between land uses. Mehlich-3 extractable P was slightly higher in cropland soils due to higher concentrations in Forestdale and Sharkey soils. Dundee, Forestdale, and Sharkey cropland soils showed significant associations between Mehlich-3-extractable iron (Fe) and P. Ratios of total carbon (TC) to total nitrogen (C:N) and TC to P (C:P) were consistent across all sampled soil series but differed between forest and cropland soils. These ratios are critical for establishing baseline soil nutrient values in simulation models and can be used to improve water quality model simulations that help guide P management in the MAP. As Sharpley routinely demonstrated, understanding sources of P is critical for developing an appropriate management strategy. This study provides critical knowledge on soil P dynamics in the MAP region., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA.)

Objectives: This systematic literature review aimed to explore the effects of head and neck cancer (HNC) on relationship intimacy in adults and identify the current support available to patients with HNC and their partners in relation to relationship intimacy., Methods: Seven databases (CINAHL, Pubmed, Scopus, Web of Science, SocINDEX, PsycARTICLES, Psychology, and Behavioural Science Collection) were searched using grouped terms "head and neck cancer and intimacy" and "head and neck cancer and support." Studies written in English to assess adult patients with HNC and its effects on relationship intimacy and studies assessing the use of intimacy-specific support tools/methods were included. The review protocol was registered in June 2022 with PROSPERO ID: CRD42022329614., Results: Thirty publications were included within the review. Six topics emerged: relationships, communication, sexual interest, barriers, couples-based communication intervention strategies, and assessment tools. While there were positive dyadic changes observed, many patients reported negative experiences relating to changes in relationship roles, sexual issues, and poor communication with partners and health care professionals that affected intimacy. There were 5 interventions identified; of those, the results varied, with some improvements noted in psychological well-being but not necessarily sexual interest and enjoyment., Conclusions: HNC profoundly affects relationship intimacy. However, both patients and health care professionals find it challenging to discuss these issues, often leaving it an unmet need. Appropriate training and development for health care professionals that facilitate communication between clinician and patient are necessary to support conversations on intimacy needs., Implications for Nursing Practice: There exists a need for patients to receive support in relation to intimacy following diagnosis and treatment, and the evidence suggests that this may be more effective post-treatment and from health care professionals who are appropriately trained. Couples' communication interventions may prove useful, but further research is required on the efficacy of combining both psychological and sexual support together., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Cardiovascular disease (CVD) risk is increased in SLE and underestimated by general population prediction algorithms. We aimed to develop a novel SLE-specific prediction tool, SLECRISK, to provide a more accurate estimate of CVD risk in SLE., Methods: We studied patients in the Brigham and Women's Hospital SLE cohort. We collected one-year baseline data including the presence of traditional CVD factors and SLE-related features at cohort enrollment. Ten-year follow-up for the first major adverse cardiovascular event (MACE; myocardial infarction (MI), stroke, or cardiac death) began at day +1 following the baseline period (index date). ICD-9/10 codes identified MACE were adjudicated by board-certified cardiologists. Least absolute shrinkage and selection operator regression selected SLE-related variables to add to the American College of Cardiology/American Heart Association (ACC/AHA) Pooled Cohort Risk Equations 10-year risk Cox regression model. Model fit statistics and performance (sensitivity, specificity, positive/negative predictive value, c-statistic) for predicting moderate/high 10-year risk (≥7.5 %) of MACE were assessed and compared to ACC/AHA, Framingham risk score (FRS), and modified FRS (mFRS). Optimism adjustment internal validation was performed using bootstrapping., Results: We included 1,243 patients with 90 MACEs (46 MIs, 36 strokes, 19 cardiac deaths) over 8946.5 person-years of follow-up. SLE variables selected for the new prediction algorithm (SLECRISK) were SLE activity (remission/mild vs. moderate/severe), disease duration (years), creatinine (mg/dL), anti-dsDNA, anti-RNP, lupus anticoagulant, anti-Ro positivity, and low C4. The sensitivity for detecting moderate/high-risk (≥7.5 %) of MACE using SLECRISK was 0.74 (95 %CI: 0.65, 0.83), which was better than the sensitivity of the ACC/AHA model (0.38 (95 %CI: 0.28, 0.48)). It also identified 3.4-fold more moderate/high-risk patients than the ACC/AHA. Patients who were moderate/high-risk according to SLECRISK but not ACC/AHA, were more likely to be young women with severe SLE and few other traditional CVD risk factors. Model performance between SLECRISK, FRS, and mFRS were similar., Conclusion: The novel SLECRISK tool is more sensitive than the ACC/AHA for predicting moderate/high 10-year risk for MACE and may be particularly useful in predicting risk for young females with severe SLE. Future external validation studies utilizing cohorts with more severe SLE are needed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Dr. Choi has consulted for Celltrion, Werfen, Organon, MitogenDx, AstraZeneca, and Mallinckrodt Canada Inc. Dr. Everett has grants from Novo Nordisk and has consulted for Ipsen Pharmaceuticals, Eli Lilly and Company, Janssen, Novo Nordisk, and Roche Diagnostics. Dr. Costenbader has consulted for or collaborated on research projects with Glaxo Smith Kline, Gilead, CabalettaBio, Exagen Diagnostics, Eli Lilly, Merck, Astra Zeneca and Neutrolis (less than $10,000 each). Dr. Weber has consulted for Bristol-Myers Squibb(BMS), Horizon Therapeutics, Kiniksa, and Novo Nordisk., (Copyright © 2024. Published by Elsevier Inc.)

Background: Older cancer survivors in general are at greater risk for cancer-related cognitive impairment (CRCI), yet few studies have explored its association with health outcomes. This study examined the association between subjective and objective measures of cognitive function and physical function, frailty, and quality of life (QoL) among older breast cancer survivors., Materials and Methods: Older breast cancer survivors who reported cognitive concerns completed surveys on patient-reported cognitive function, physical function, frailty, and QoL as well as objective tests of visuospatial working memory and sustained attention. Data were analyzed using descriptive statistics and separate linear regression models., Results: A total of 219 female breast cancer survivors completed the study. Perceived cognitive abilities were associated with better physical function, frailty, and QoL ( p ≤ 0.001) while cognitive concerns were negatively related with these metrics ( p ≤ 0.001). Poorer visuospatial working memory and sustained attention were linked to increased frailty ( p ≤ 0.001-0.01), whereas poorer sustained attention was associated with poorer physical function ( p < 0.01)., Conclusions: Older breast cancer survivors with perceived cognitive impairment and poorer cognitive performance reported poorer physical functioning, increased frailty, and poorer QoL. These findings underscore the importance of assessing cognitive concerns and their associated outcomes in older breast cancer survivors.

Background: Individuals who have metastatic cancer experience substantial physical and psychological distress (e.g., pain, depression, anxiety) from their disease and its treatment compared to patients with less advanced disease. As the burden of symptoms varies over time, ecological momentary assessment (EMA) may be used to better understand patients' symptom trajectories, complimenting traditional longitudinal data collection methods. However, few have used EMA in patients with metastatic disease. The current study adds to the existing literature by exploring interrelated, common cancer-related symptoms of pain, anxiety, and depression and use of cannabis-based products, opioid medications, other (nonopioid) pain medications, and medications for anxiety or depression., Methods: An eight-day prospective observational feasibility study was conducted among 50 patients with metastatic cancer recruited from seven solid cancer clinics at The Ohio State University Comprehensive Cancer Center. Participants completed a week of interval-contingent mobile EMA, administered daily at 9 a.m., 3 p.m., and 8 p.m., and a comprehensive interviewer-administered questionnaire on Day 8. Participants were queried on their symptom burden and management strategies (i.e., use of medications and cannabis). We considered EMA to be feasible if a priori retention (80%) and adherence goals (75%) were met., Results: Seventy-nine percent of eligible patients contacted enrolled in the study ( n  = 50 of 63). Among those enrolled, 92% were retained through Day 8 and 80% completed >90% of EMAs, exceeding a priori objectives. Participants' average pain, anxiety, and depressive symptoms across the week of EMA ranged from 1.7 to 1.8 (1 to 5 scale). Symptoms varied little by day or time of administration. On Day 8, significant proportions of participants reported past-week use of medications and cannabis for symptom management., Conclusions: Participants exceeded a priori adherence and retention objectives, indicating that mobile EMA is feasible among metastatic cancer patients, addressing a gap in the existing literature and informing future research. Restricting eligibility to participants with a minimum cutoff of symptom burden may be warranted to increase observations of symptom variability and provide opportunities for future health interventions. Future research is needed to test the acceptability and quality of data over a longer study period in this patient population., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Background: The objective of this study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of PF‑06835375, a potent selective afucosyl immunoglobulin G1 antibody targeting C-X-C chemokine receptor type 5 (CXCR5) that potentially depletes B cells, follicular T helper (Tfh) cells, and circulating Tfh-like (cTfh) cells, in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA)., Methods: This first-in-human, multicenter, double-blind, sponsor-open, placebo-controlled Phase 1 study recruited patients aged 18-70 years with SLE or RA. In Part A, patients received single doses of intravenous PF-06835375 (dose range: 0.03-6 mg) or placebo in six sequential single ascending dose (SAD) cohorts. In Part B, patients received repeat doses of subcutaneous PF-06835375 (dose range: 0.3-10 mg) or placebo on Days 1 and 29 in five multiple ascending dose (MAD) cohorts. Tetanus/Diphtheria (Td) and Meningococcal B (MenB/Trumenba™) vaccines were administered at Day 4 (Td and MenB) and Week 8 (MenB only) to assess PF-06835375 functional effects. Endpoints included treatment-emergent adverse events (TEAEs), pharmacokinetic parameters, pharmacodynamic effects on B and cTfh cells, and biomarker counts, vaccine response, and exploratory differential gene expression analysis. Safety, pharmacokinetic, and pharmacodynamic endpoints are summarized descriptively. The change from baseline of B and Tfh cell-specific genes over time was calculated using a prespecified mixed-effects model, with a false discovery rate < 0.05 considered statistically significant., Results: In total, 73 patients were treated (SAD cohorts: SLE, n = 17; RA, n = 14; MAD cohorts: SLE, n = 22; RA, n = 20). Mean age was 53.3 years. Sixty-two (84.9%) patients experienced TEAEs (placebo n = 17; PF-06835375 n = 45); most were mild or moderate. Three (9.7%) patients experienced serious adverse events. Mean t 1/2 ranged from 3.4-121.4 h (SAD cohorts) and 162.0-234.0 h (MAD cohorts, Day 29). B and cTfh cell counts generally showed dose-dependent reductions across cohorts (range of mean maximum depletion: 67.3-99.3%/62.4-98.7% [SAD] and 91.1-99.6%/89.5-98.1% [MAD], respectively). B cell-related genes and pathways were significantly downregulated in patients treated with PF-06835375., Conclusions: These data support further development of PF-06835375 to assess the clinical potential for B and Tfh cell depletion as a treatment for autoimmune diseases., Trial Registration: ClinicalTrials.gov identifier: NCT03334851., (© 2024. The Author(s).)

Throughout the COVID-19 pandemic, populations of color have been disproportionately impacted, with higher rates of infection, hospitalization, and mortality, compared to non-Hispanic whites. These disparities in health outcomes are likely related to a combination of factors including underlying socioeconomic inequities, unequal access to healthcare, higher rates of employment in essential or public-facing occupations, language barriers, and COVID-19 vaccine inequities. In this manuscript the authors discuss strategies of how one local health department responded to vaccine inequities to better serve historically excluded communities throughout the early stages of the COVID-19 pandemic in 2021. These efforts helped increase vaccination rates in marginalized communities, primarily in the Black or African American population in Durham County, North Carolina., (© 2023. W. Montague Cobb-NMA Health Institute.)

Objectives: To describe adherence to the American Academy of Pediatrics' (AAP) 2017 clinical practice guidelines for follow-up after high blood pressure (BP) screening by pediatric and family medicine providers in a Massachusetts health care system and to assess differences in receipt of follow-up according to child- and clinic-level factors., Methods: Electronic health record data were analyzed for children aged 3 to 17years who had an outpatient primary care visit during 2018 with a high BP screening (according to AAP guidelines). We classified AAP guideline adherent follow-up as BP follow-up within 6months after an elevated finding (+2-week buffer) and within 2weeks after a hypertensive finding (+2-week buffer). Differences in receipt of guideline adherent follow-up by child- and clinic-level factors were assessed via multilevel mixed effects logistic regression models., Results: The median age of the 4563 included children was 12years and 43% were female. Overall, guideline adherent follow-up was received by 17.7% of children within the recommended time interval; 27.4% for those whose index BP was elevated and 5.4% for those whose index BP was hypertensive. Modeling revealed older children and those belonging to clinics with more providers, smaller patient panels, and smaller proportion of Medicaid patients were more likely to receive adherent follow-up., Conclusions: Few children received guideline adherent BP follow-up and most differences in adherence were related to clinic resources. System-level interventions are needed to improve BP follow-up., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors have received support from the following for the production of this manuscript: National Heart, Lung, And Blood Institute of the National Institutes of Health under Award Number F31HL164126., (Copyright © 2024 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Background: Accumulation of tau leads to neuroinflammation and neuronal cell death in tauopathies, including Alzheimer's disease. As the disease progresses, there is a decline in brain energy metabolism. However, the role of tau protein in regulating lipid metabolism remains less characterized and poorly understood., Methods: We used a transgenic rat model for tauopathy to reveal metabolic alterations induced by neurofibrillary pathology. Transgenic rats express a tau fragment truncated at the N- and C-terminals. For phenotypic profiling, we performed targeted metabolomic and lipidomic analysis of brain tissue, CSF, and plasma, based on the LC-MS platform. To monitor disease progression, we employed samples from transgenic and control rats aged 4, 6, 8, 10, 12, and 14 months. To study neuron-glia interplay in lipidome changes induced by pathological tau we used well well-established multicomponent cell model system. Univariate and multivariate statistical approaches were used for data evaluation., Results: We showed that tau has an important role in the deregulation of lipid metabolism. In the lipidomic study, pathological tau was associated with higher production of lipids participating in protein fibrillization, membrane reorganization, and inflammation. Interestingly, significant changes have been found in the early stages of tauopathy before the formation of high-molecular-weight tau aggregates and neurofibrillary pathology. Increased secretion of pathological tau protein in vivo and in vitro induced upregulated production of phospholipids and sphingolipids and accumulation of lipid droplets in microglia. We also found that this process depended on the amount of extracellular tau. During the later stages of tauopathy, we found a connection between the transition of tau into an insoluble fraction and changes in brain metabolism., Conclusion: Our results revealed that lipid metabolism is significantly affected during different stages of tau pathology. Thus, our results demonstrate that the dysregulation of lipid composition by pathological tau disrupts the microenvironment, further contributing to the propagation of pathology., (© 2024. The Author(s).)

Aims/background: We aimed to adapt, pilot and explore experiences of receiving and delivering the video feedback intervention for positive parenting (VIPP) for 2 to 6 month old babies, mothers experiencing moderate to severe perinatal mental health difficulties and perinatal mental health clinicians., Design/methods: The VIPP intervention was adapted to include developmentally appropriate activities and developmental psychoeducation for 2 to 6 month olds, alongside psychoeducation on emotion regulation, and then piloted in 14 mothers experiencing moderate to severe perinatal mental health difficulties (registration ISRCTN64237883). Observational and self-reported pre-post outcome data on parenting and parent-infant mental health was collected, and post-intervention qualitative interviews were conducted with participating mothers and clinicians., Results: Consent (67%), intervention completion (79%) and follow-up rates (93%) were high. Effect sizes on pre-post outcome measures indicated large improvements in parenting confidence and perceptions of the parent-infant relationship, and a medium-size improvement in maternal sensitivity. In qualitative interviews, clinicians and mothers described how mothers' initial anxieties about being filmed were allayed through receiving positive and strengths-focussed feedback, boosting their self-confidence, and that the video feedback facilitated identification of young babies' subtle behavioural cues and moments of mother-infant connection. Streamlining the information provided on maternal emotion regulation, and allowing increased use of clinical judgement to tailor intervention delivery, were suggested to optimise intervention feasibility and acceptability., Conclusion: It is feasible and acceptable to implement VIPP with very young babies and their mothers experiencing perinatal mental health difficulties. A fully powered randomised controlled trial is required to establish intervention efficacy.

Ritlecitinib is a small molecule in clinical development that covalently and irreversibly inhibits Janus kinase 3 (JAK3) and the TEC family of kinases (BTK, BMX, ITK, TXK, and TEC). This phase 1, open-label, parallel-group study assessed target occupancy and functional effects of ritlecitinib on JAK3 and TEC family kinases in healthy participants aged 18-60 years who received 50 or 200 mg single doses of ritlecitinib on day 1. Blood samples to assess ritlecitinib pharmacokinetics, target occupancy, and pharmacodynamics were collected over 48 hours. Target occupancy was assessed using mass spectroscopy. Functional inhibition of JAK3-dependent signaling was measured by the inhibition of the phosphorylation of its downstream target signal transducer and activator of transcription 5 (pSTAT5), following activation by interleukin 15 (IL-15). The functional inhibition of Bruton's tyrosine kinase (BTK)-dependent signaling was measured by the reduction in the upregulation of cluster of differentiation 69 (CD69), an early marker of B-cell activation, following treatment with anti-immunoglobulin D. Eight participants received one 50 mg ritlecitinib dose and 8 participants received one 200 mg dose. Ritlecitinib plasma exposure increased in an approximately dose-proportional manner from 50 to 200 mg. The maximal median JAK3 target occupancy was 72% for 50 mg and 64% for 200 mg. Ritlecitinib 50 mg had >94% maximal target occupancy of all TEC kinases, except BMX (87%), and 200 mg had >97% for all TEC kinases. For BTK and TEC, ritlecitinib maintained high target occupancy throughout a period of 48 hours. Ritlecitinib reduced pSTAT5 levels following IL-15- and BTK-dependent signaling in a dose-dependent manner. These target occupancy and functional assays demonstrate the dual inhibition of the JAK3- and BTK-dependent pathways by ritlecitinib. Further studies are needed to understand the contribution to clinical effects of inhibiting these pathways., (© 2023 Pfizer Inc. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Symptoms such as pain, nausea, and anxiety are common in individuals with cancer. Treatment of these issues is often challenging. Cannabis products may be helpful in reducing the severity of these symptoms. While some studies include data on the prevalence of cannabis use among patients with cancer, detailed data remain limited, and none have reported the prevalence of cannabidiol (CBD) use in this population. Adult patients with cancer attending eight clinics at a large, NCI-designated Comprehensive Cancer Center completed a detailed, cannabis-focused questionnaire between 2021 and 2022. Eligible participants were diagnosed with invasive cancer and treated in the past 12 months. Summary statistics were calculated to describe the sample regarding cannabis use. Approximately 15% (n = 142) of consented patients (n = 934) reported current cannabis use (defined as use within the past 12 months). Among which, 75% reported cannabis use in the past week. Among current cannabis users, 39% (n = 56; 6% overall) used CBD products. Current users reported using cannabis a median of 4.5 (interquartile range: 0.6–7.0) days/week, 2.0 (1.0–3.0) times per use/day, and for 3 years (0.8–30.0). Use patterns varied by route of administration. Patients reported moderate to high relief of symptoms with cannabis use. This study is the most detailed to date in terms of cannabis measurement and provides information about the current state of cannabis use in active cancer. Future studies should include complete assessments of cannabis product use, multiple recruitment sites, and diverse patient populations., Significance: Clinicians should be aware that patients are using cannabis products and perceive symptom relief with its use., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Introduction: This study aimed to describe adolescent, parent, and clinician ideas for enhancing adolescent decision-making involvement (DMI) during clinic visits for chronic illness., Method: Adolescents who recently attended a follow-up visit for a chronic illness, their parents, and clinicians were interviewed. Participants completed semistructured interviews; transcripts were coded and analyzed in NVivo. Responses to questions about ideas to increase adolescent DMI were reviewed and sorted into categories and themes., Results: There were five themes: (1) adolescents need to understand their condition and regimen, (2) adolescents and parents should prepare before the visit, (3) clinicians and adolescents should have one-on-one time, (4) opportunities for condition-specific peer support would be helpful, and (5) clinicians and parents should engage in specific communication behaviors., Discussion: Findings from this study highlight potential clinician-, parent-, and adolescent-focused strategies for enhancing adolescent DMI. Clinicians, parents, and adolescents may need specific guidance on how to enact new behaviors., (Copyright © 2023 National Association of Pediatric Nurse Practitioners. Published by Elsevier Inc. All rights reserved.)

The 16 th Workshop on Recent Issues in Bioanalysis (16 th WRIB) took place in Atlanta, GA, USA on September 26-30, 2022. Over 1000 professionals representing pharma/biotech companies, CROs, and multiple regulatory agencies convened to actively discuss the most current topics of interest in bioanalysis. The 16 th WRIB included 3 Main Workshops and 7 Specialized Workshops that together spanned 1 week in order to allow exhaustive and thorough coverage of all major issues in bioanalysis, biomarkers, immunogenicity, gene therapy, cell therapy and vaccines. Moreover, in-depth workshops on ICH M10 BMV final guideline (focused on this guideline training, interpretation, adoption and transition); mass spectrometry innovation (focused on novel technologies, novel modalities, and novel challenges); and flow cytometry bioanalysis (rising of the 3rd most common/important technology in bioanalytical labs) were the special features of the 16 th edition. As in previous years, WRIB continued to gather a wide diversity of international, industry opinion leaders and regulatory authority experts working on both small and large molecules as well as gene, cell therapies and vaccines to facilitate sharing and discussions focused on improving quality, increasing regulatory compliance, and achieving scientific excellence on bioanalytical issues. This 2022 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2022 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 2) covers the recommendations on LBA, Biomarkers/CDx and Cytometry. Part 1 (Mass Spectrometry and ICH M10) and Part 3 (Gene Therapy, Cell therapy, Vaccines and Biotherapeutics Immunogenicity) are published in volume 15 of Bioanalysis, issues 16 and 14 (2023), respectively.

Purpose: We developed and validated a measure assessing quality of life (QOL) through importance, attainability, and discrepancy of life goals among adolescents and young adults (AYA) with and without cancer. A specific goal-based QOL measure for AYA fills a critical gap in knowledge for AYA who are at a unique life stage, which may include shifts in priorities and goals., Methods: Through review of our existing AYA databases on goals, the literature, and cognitive interviews we developed the MAYA-GQOL. Items were administered to AYA with cancer (on/off treatment) (n = 124) and healthy AYA controls (n = 103) aged 15-29 years old. Psychometric analyses for comparison with existing QOL measures and discrepancies in perceived importance/attainability of goals were examined., Results: An item pool of 700 goals, based on prior research, was refined to 173 goals across nine categories: academic, administrative, body, health, job, leisure, interpersonal, intrapersonal, and religion. Validation between the MAYA-GQOL and existing QOL measures was supported. AYA survivors reported fewer overall current goals and fewer administrative, interpersonal, leisure, and religious goals. AYA survivors rated body goal importance significantly higher than healthy controls and intrapersonal goal importance significantly lower. Little discrepancy in importance and attainability across AYA was found., Conclusions: The MAYA-GQOL represents an innovative way of measuring QOL among AYA by focusing on the relative importance, attainability, and discrepancy of developmentally appropriate goals. The MAYA-GQOL can identify areas of resilience and competence via assessment of important and attainable goals and can further assess how AYA with chronic illness are functioning relative to peers on goal domains relevant to the AYA developmental period., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Blocking chemokine receptor C-C chemoattractant cytokine (chemokine) receptor (CCR) 6-dependent T cell migration has therapeutic promise in inflammatory diseases. PF-07054894 is a novel CCR6 antagonist that blocked only CCR6, CCR7, and C-X-C chemoattractant cytokine (chemokine) receptor (CXCR) 2 in a β -arrestin assay panel of 168 G protein-coupled receptors. Inhibition of CCR6-mediated human T cell chemotaxis by (R)-4-((2-(((1,4-Dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (PF-07054894) was insurmountable by CCR6 ligand, C-C motif ligand (CCL) 20. In contrast, blockade of CCR7-dependent chemotaxis in human T cells and CXCR2-dependent chemotaxis in human neutrophils by PF-07054894 were surmountable by CCL19 and C-X-C motif ligand 1, respectively. [ 3 H]-PF-07054894 showed a slower dissociation rate for CCR6 than for CCR7 and CXCR2 suggesting that differences in chemotaxis patterns of inhibition could be attributable to offset kinetics. Consistent with this notion, an analog of PF-07054894 with fast dissociation rate showed surmountable inhibition of CCL20/CCR6 chemotaxis. Furthermore, pre-equilibration of T cells with PF-07054894 increased its inhibitory potency in CCL20/CCR6 chemotaxis by 10-fold. The functional selectivity of PF-07054894 for inhibition of CCR6 relative to CCR7 and CXCR2 is estimated to be at least 50- and 150-fold, respectively. When administered orally to naïve cynomolgus monkeys, PF-07054894 increased the frequency of CCR6 + peripheral blood T cells, suggesting that blockade of CCR6 inhibited homeostatic migration of T cells from blood to tissues. PF-07054894 inhibited interleukin-23-induced mouse skin ear swelling to a similar extent as genetic ablation of CCR6. PF-07054894 caused an increase in cell surface CCR6 in mouse and monkey B cells, which was recapitulated in mouse splenocytes in vitro. In conclusion, PF-07054894 is a potent and functionally selective CCR6 antagonist that blocks CCR6-mediated chemotaxis in vitro and in vivo. SIGNIFICANCE STATEMENT: The chemokine receptor, C-C chemoattractant cytokine (chemokine) receptor 6 (CCR6) plays a key role in the migration of pathogenic lymphocytes and dendritic cells into sites of inflammation. (R)-4-((2-(((1,4-Dimethyl-1H-pyrazol-3-yl)(1-methylcyclopentyl)methyl)amino)-3,4-dioxocyclobut-1-en-1-yl)amino)-3-hydroxy-N,N-dimethylpicolinamide (PF-07054894) is a novel CCR6 small molecule antagonist that illustrates the importance of binding kinetics in achieving pharmacological potency and selectivity. Orally administered PF-07054894 blocks homeostatic and pathogenic functions of CCR6, suggesting that it is a promising therapeutic agent for the treatment of a variety of autoimmune and inflammatory diseases., (Copyright © 2023 by The Author(s).)