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Background: Mismatch repair deficiency (dMMR) and microsatellite instability-high (MSI-H) occur in a subset of cancers and have been shown to confer sensitivity to immune checkpoint inhibition (ICI); however, there is a lack of prospective data in urothelial carcinoma (UC). Methods and analysis: We performed a systematic review to estimate the prevalence of dMMR and MSI-H in UC, including survival and clinical outcomes. We searched for studies published up to 26 October 2022 in major scientific databases. We screened 1745 studies and included 110. Meta-analyses were performed if the extracted data were suitable. Results: The pooled weighted prevalences of dMMR in bladder cancer (BC) and upper tract UC (UTUC) were 2.30% (95% CI 1.12% to 4.65%) and 8.95% (95% CI 6.81% to 11.67%), respectively. The pooled weighted prevalences of MSI-H in BC and UTUC were 2.11% (95% CI 0.82% to 5.31%) and 8.36% (95% CI 5.50% to 12.53%), respectively. Comparing localised versus metastatic disease, the pooled weighted prevalences for MSI-H in BC were 5.26% (95% CI 0.86% to 26.12%) and 0.86% (95% CI 0.59% to 1.25%), respectively; and in UTUC, they were 18.04% (95% CI 13.36% to 23.91%) and 4.96% (95% CI 2.72% to 8.86%), respectively. Cumulatively, the response rate in dMMR/MSI-H metastatic UC treated with an ICI was 22/34 (64.7%) compared with 1/9 (11.1%) with chemotherapy. Conclusion: Both dMMR and MSI-H occur more frequently in UTUC than in BC. In UC, MSI-H occurs more frequently in localised disease than in metastatic disease. These biomarkers may predict sensitivity to ICI in metastatic UC and resistance to cisplatin-based chemotherapy.
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Background: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a genetic disorder characterized by bone marrow failure and systemic inflammation, putting patients at risk for infections. This study comprehensively examines the prevalence of opportunistic infections in patients with VEXAS, evaluating their impact on clinical outcomes and potential preventive measures. Methods: Patients with confirmed VEXAS were included. Survival analysis and logistic regression were used to identify associations between opportunistic infections and mortality. Infection rates (IRs) for Pneumocystis jirovecii pneumonia (PJP) and alphaherpesviruses were calculated over a prospective 8-month observation period in relationship to prophylaxis. Results: Of 94 patients with VEXAS, 6% developed PJP; 15% had alphaherpesvirus reactivation, with varicella zoster virus (VZV) being the most common herpesvirus; and 10% contracted a nontuberculous mycobacterial (NTM) infection. Risk of death was significantly increased per month following a diagnosis of PJP (hazard ratio [HR], 72.41 [95% confidence interval {CI}, 13.67-533.70]) or NTM (HR, 29.09 [95% CI, 9.51-88.79]). Increased odds for death were also observed in patients with a history of herpes simplex virus (HSV) reactivation (odds ratio [OR], 12.10 [95% CI, 1.29-114.80]) but not in patients with VZV (OR, 0.89 [95% CI, .30-2.59]). Prophylaxis for PJP (IR, 0.001 vs 0 per person-day, P < .01) and VZV (IR, 0.006 vs 0 per person-day, P = .04) markedly decreased infection rates with a number needed to treat of 4 and 7, respectively. Conclusions: Opportunistic infections are common in patients with VEXAS. Patients who develop PJP, HSV, or NTM are at increased risk for death. Prophylaxis against PJP and VZV is highly effective.
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BACKGROUND: Niemann-Pick disease, type C1 (NPC1) is a rare lysosomal disorder with progressive neurological manifestations, historically recognized as a pediatric disease. However, awareness of the adult-onset (AO) subtype is increasing, often with non-specific symptoms leading to delayed and misdiagnosis. Dysphagia, commonly recognized as a clinical morbidity in NPC1, raises concerns for swallowing safety and aspiration risk. This study aims to characterize swallowing function in AO NPC1, addressing the gap in understanding and clinical management. METHODS: Fourteen AO NPC1 individuals in a prospective natural history study (NCT00344331) underwent comprehensive assessments, including history and physical examinations utilizing the NPC1 severity rating scale, videofluoroscopic swallowing studies with summary interpretive analysis, and cerebrospinal fluid (CSF) collection for biomarker evaluation at baseline visit. Descriptive statistics and multivariate statistical modeling were employed to analyze NPC1 disease covariates, along with the American Speech-Language-Hearing Association National Outcome Measure (ASHA-NOMS) and the NIH Penetration Aspiration Scale (NIH-PAS). RESULTS: Our cohort, comprised of 14 predominately female (n = 11, 78.6%) individuals, had an average age of 43.1 ± 16.7 years at the initial visit. Overall, our AO patients were able to swallow independently with no/minimal cueing, with 6 (43%) avoiding specific food items or requiring more time. Upon risk analysis of aspiration, the cohort demonstrated no obvious aspiration risk or laryngeal aspiration in 8 (57%), minimal risk with intermittent laryngeal penetration and retrograde excursion in 5(36%), and moderate risk (7%) in only one. Dietary modifications were recommended in 7 (50%), particularly for liquid viscosities (n = 6, 43%) rather than solids (n = 3, 21%). No significant correlations were identified between swallowing outcomes and NPC1-related parameters or CSF biomarkers. CONCLUSION: Despite the heterogeneity in NPC1 presentation, the AO cohort displayed functional swallowing abilities with low aspiration risk with some participants still requiring some level of dietary modifications. This study emphasizes the importance of regular swallowing evaluations and management in AO NPC1 to address potential morbidities associated with dysphagia such as aspiration. These findings provide clinical recommendations for the assessment and management of the AO cohort, contributing to improved care for these individuals.
Subject(s)
Deglutition Disorders , Deglutition , Niemann-Pick Disease, Type C , Humans , Niemann-Pick Disease, Type C/diagnosis , Niemann-Pick Disease, Type C/physiopathology , Female , Adult , Male , Deglutition/physiology , Deglutition Disorders/physiopathology , Middle Aged , Prospective Studies , Young AdultABSTRACT
OBJECTIVES: What are the Canadian public's understanding of and views toward medical assistance in dying (MAID) in persons refusing recommended treatment or lacking access to standard treatment or resources? DESIGN/SETTING: An online survey assessed knowledge of and support for Canadian MAID law, and views about four specific scenarios in a two (medical or psychiatric) by two (treatment refusal or lack of access) design. PARTICIPANTS: A quota sample (N=2140) matched to the 2021 Canadian census by age, gender, income, education and province. MAIN OUTCOMES: Participants' level of support for MAID in general and in the four specific scenarios. RESULTS: Only 12.1% correctly answered ≥4 of 5 knowledge questions about the MAID law; only 19.2% knew terminal illness is not required and 20.2% knew treatment refusal is compatible with eligibility. 73.3% of participants expressed support for the MAID law in general, matching a nationally representative poll that used the same question. 40.4% of respondents supported MAID for mental illnesses. Support for MAID in the scenarios depicting refusal or lack of access to treatment ranged from 23.2% (lack of access in medical condition) to 32.0% (treatment refusal in medical illness). Older age, more education, higher income, lower religious attendance or being white was associated with greater support for MAID in general but was either negatively associated or not associated with support for MAID in the four refusal or lack of access scenarios. CONCLUSIONS: Most Canadians support the current MAID law but appear unaware that MAID cases they do not support are compatible with that law. The lower support for MAID in the four scenarios cuts across sociodemographics. The gap between current policy and public opinion warrants further study. For jurisdictions debating MAID, opinion surveys may need to go beyond assessing general attitudes, and target knowledge and views regarding implications of legalisation.
Subject(s)
Public Opinion , Suicide, Assisted , Humans , Canada , Male , Female , Middle Aged , Adult , Suicide, Assisted/legislation & jurisprudence , Suicide, Assisted/statistics & numerical data , Aged , Surveys and Questionnaires , Young Adult , Adolescent , Treatment Refusal/statistics & numerical data , Treatment Refusal/legislation & jurisprudence , Health Knowledge, Attitudes, Practice , Health Services AccessibilityABSTRACT
BACKGROUND: Neurofilament proteins have been implicated to be altered in amyotrophic lateral sclerosis (ALS). The objectives of this study were to assess the diagnostic and prognostic utility of neurofilaments in ALS. METHODS: Studies were conducted in electronic databases (PubMed/MEDLINE, Embase, Web of Science, and Cochrane CENTRAL) from inception to 17 August 2023, and investigated neurofilament light (NfL) or phosphorylated neurofilament heavy chain (pNfH) in ALS. The study design, enrolment criteria, neurofilament concentrations, test accuracy, relationship between neurofilaments in cerebrospinal fluid (CSF) and blood, and clinical outcome were recorded. The protocol was registered with PROSPERO, CRD42022376939. RESULTS: Sixty studies with 8801 participants were included. Both NfL and pNfH measured in CSF showed high sensitivity and specificity in distinguishing ALS from disease mimics. Both NfL and pNfH measured in CSF correlated with their corresponding levels in blood (plasma or serum); however, there were stronger correlations between CSF NfL and blood NfL. NfL measured in blood exhibited high sensitivity and specificity in distinguishing ALS from controls. Both higher levels of NfL and pNfH either measured in blood or CSF were correlated with more severe symptoms as assessed by the ALS Functional Rating Scale Revised score and with a faster disease progression rate; however, only blood NfL levels were associated with shorter survival. DISCUSSION: Both NfL and pNfH measured in CSF or blood show high diagnostic utility and association with ALS functional scores and disease progression, while CSF NfL correlates strongly with blood (either plasma or serum) and is also associated with survival, supporting its use in clinical diagnostics and prognosis. Future work must be conducted in a prospective manner with standardized bio-specimen collection methods and analytical platforms, further improvement in immunoassays for quantification of pNfH in blood, and the identification of cut-offs across the ALS spectrum and controls.
Subject(s)
Amyotrophic Lateral Sclerosis , Neurofilament Proteins , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/blood , Amyotrophic Lateral Sclerosis/diagnosis , Amyotrophic Lateral Sclerosis/cerebrospinal fluid , Humans , Neurofilament Proteins/blood , Neurofilament Proteins/cerebrospinal fluid , Biomarkers/blood , Biomarkers/cerebrospinal fluid , Intermediate Filaments/metabolism , Intermediate Filaments/genetics , PrognosisABSTRACT
OBJECTIVE: To compare the diagnostic performance of [68Ga]DOTATATE PET/CT, [18F]FDG PET/CT, MRI of the spine, and whole-body CT and MRI for the detection of pheochromocytoma/paraganglioma (PPGL)-related spinal bone metastases. MATERIALS AND METHODS: Between 2014 and 2020, PPGL participants with spinal bone metastases prospectively underwent [68Ga]DOTATATE PET/CT, [18F]FDG PET/CT, MRI of the cervical-thoracolumbar spine (MRIspine), contrast-enhanced MRI of the neck and thoraco-abdominopelvic regions (MRIWB), and contrast-enhanced CT of the neck and thoraco-abdominopelvic regions (CTWB). Per-patient and per-lesion detection rates were calculated. Counting of spinal bone metastases was limited to a maximum of one lesion per vertebrae. A composite of all functional and anatomic imaging served as an imaging comparator. The McNemar test compared detection rates between the scans. Two-sided p values were reported. RESULTS: Forty-three consecutive participants (mean age, 41.7 ± 15.7 years; females, 22) with MRIspine were included who also underwent [68Ga]DOTATATE PET/CT (n = 43), [18F]FDG PET/CT (n = 43), MRIWB (n = 24), and CTWB (n = 33). Forty-one of 43 participants were positive for spinal bone metastases, with 382 lesions on the imaging comparator. [68Ga]DOTATATE PET/CT demonstrated a per-lesion detection rate of 377/382 (98.7%) which was superior compared to [18F]FDG (72.0%, 275/382, p < 0.001), MRIspine (80.6%, 308/382, p < 0.001), MRIWB (55.3%, 136/246, p < 0.001), and CTWB (44.8%, 132/295, p < 0.001). The per-patient detection rate of [68Ga]DOTATATE PET/CT was 41/41 (100%) which was higher compared to [18F]FDG PET/CT (90.2%, 37/41, p = 0.13), MRIspine (97.6%, 40/41, p = 1.00), MRIWB (95.7%, 22/23, p = 1.00), and CTWB (81.8%, 27/33, p = 0.03). CONCLUSIONS: [68Ga]DOTATATE PET/CT should be the modality of choice in PPGL-related spinal bone metastases due to its superior detection rate. CLINICAL RELEVANCE STATEMENT: In a prospective study of 43 pheochromocytoma/paraganglioma participants with spinal bone metastases, [68Ga]DOTATATE PET/CT had a superior per-lesion detection rate of 98.7% (377/382), compared to [18F]FDG PET/CT (p < 0.001), MRI of the spine (p < 0.001), whole-body CT (p < 0.001), and whole-body MRI (p < 0.001). KEY POINTS: ⢠Data regarding head-to-head comparison between functional and anatomic imaging modalities to detect spinal bone metastases in pheochromocytoma/paraganglioma are limited. ⢠[68Ga]DOTATATE PET/CT had a superior per-lesion detection rate of 98.7% in the detection of spinal bone metastases associated with pheochromocytoma/paraganglioma compared to other imaging modalities: [18]F-FDG PET/CT, MRI of the spine, whole-body CT, and whole-body MRI. ⢠[68Ga]DOTATATE PET/CT should be the modality of choice in the evaluation of spinal bone metastases associated with pheochromocytoma/paraganglioma.
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Context: Patients with primary adrenal insufficiency due to congenital adrenal hyperplasia (CAH) are at risk for adrenal crisis during infectious illnesses. Increased risk of infection including COVID-19 has been variably reported. Objective: To evaluate COVID-19 illness outcomes and stress dose practices in a large cohort of patients with CAH during the first two years of the pandemic and compare observations of COVID-19 infection in patients with CAH to the general USA population. Methods: Between March 2020 and November 2022, patients with CAH followed at the National Institutes of Health Clinical Center were queried about COVID-19 infection during their routine visits. Cases of COVID-19 were compared to controls. COVID-19 infection rates and symptoms were compared to general USA population data from the Centers for Disease Control and Prevention. Results: Of 168 patient visits, there were 54 (32%) cases of COVID-19 infection, and 15 (28%) were pediatric. Overall an association was found between acquiring COVID-19 and obesity (p=0.018), and adults acquiring COVID-19 were on lower doses of fludrocortisone (p=0.008). Fewer cases of COVID-19 infection were reported in those receiving hydrocortisone or modified-release hydrocortisone compared to longer acting glucocorticoids (p=0.0018). In our CAH population, the pattern of COVID-19 infection rates and COVID-related symptomatology were similar to those observed in the general USA population. Most patients with the presumed alpha variant reported anosmia and ageusia, while gastrointestinal symptoms were commonly reported during the delta and omicron waves. Stress dosing occurred in 30/54 cases, and 7 received parenteral hydrocortisone. Two hospitalizations occurred; one pediatric and one adult, both with co-morbidities. There were 5 emergency room visits and no reported deaths. Conclusion: Patients with CAH with close follow-up do not appear to be at increased risk of acquiring COVID-19 or to have a more severe course of COVID-19 compared to the general USA population. Obesity may increase risk of acquiring COVID-19 in patients with CAH, and overall infection risk may be lower in those receiving short-acting and circadian glucocorticoid replacement therapy. Established age-appropriate guidelines for stress dosing during infectious illnesses should be used for patients with CAH and COVID-19. COVID-19 specific guidelines are not indicated. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT00250159.
Subject(s)
Adrenal Hyperplasia, Congenital , COVID-19 , Adult , Child , Humans , Adrenal Hyperplasia, Congenital/complications , Adrenal Hyperplasia, Congenital/drug therapy , Adrenal Hyperplasia, Congenital/epidemiology , COVID-19/complications , COVID-19/epidemiology , Glucocorticoids/therapeutic use , Hydrocortisone/therapeutic use , Obesity/complications , Obesity/epidemiology , Obesity/drug therapy , SARS-CoV-2 , United States , Case-Control StudiesABSTRACT
CONTEXT: Children with congenital adrenal hyperplasia (CAH) are at risk for early puberty. Gonadotropin-releasing hormone analog (GnRHa) is frequently used and can decrease bone mineral density (BMD). OBJECTIVE: Our aim was to investigate the effect of GnRHa therapy on BMD in a longitudinal study of patients with CAH spanning both childhood and adulthood. DESIGN AND SETTING: Sixty-one patients with classic CAH due to 21-hydroxylase deficiency (20 treated with GnRHa) were followed with dual-energy X-ray absorptiometry (DXA) scans at puberty onset, attainment of adult height, and during early adulthood. MAIN OUTCOME MEASURES: Whole body, lumbar spine, femoral neck, total hip, and distal radius BMD z-score at adult height. Longitudinal BMD and adult height were also assessed. RESULTS: Twenty patients received GnRHa for an average of 4.5 ± 2 years. There were no differences in BMD between GnRHa-treated and -untreated groups at adult height for all sites. Overall, the follow-up DXA during early adulthood showed decreases in BMD z-scores for whole body (P = .01), lumbar spine (P < .0001), femoral neck (P = .06), total hip (P = .009), and distal radius (P = .05). GnRHa treatment correlated with improved height outcomes compared to predicted height at puberty onset after adjusting for midparental height (P = .02). Patients in both groups achieved similar adult height. CONCLUSION: In children with CAH, GnRHa does not compromise BMD. However, BMD decreases with time and during the second and third decades of life is a possible effect of chronic supraphysiologic glucocorticoids. Children with CAH who experience early puberty benefit from GnRHa treatment as evidenced by the positive effect on height.
Subject(s)
Adrenal Hyperplasia, Congenital , Puberty, Precocious , Child , Adult , Humans , Adrenal Hyperplasia, Congenital/complications , Adrenal Hyperplasia, Congenital/drug therapy , Bone Density , Longitudinal Studies , Gonadotropins , Lumbar Vertebrae , Gonadotropin-Releasing Hormone , Body HeightABSTRACT
Introduction: Pediatric obesity has steadily increased in recent decades. Large-scale genome-wide association studies (GWAS) conducted primarily in Eurocentric adult populations have identified approximately 100 loci that predispose to obesity and type II diabetes. GWAS in children and individuals of non-European descent, both disproportionately affected by obesity, are fewer. Rare syndromic and monogenic obesities account for only a small portion of childhood obesity, so understanding the role of other genetic variants and their combinations in heritable obesities is key to developing targeted and personalized therapies. Tight and responsive regulation of the cAMP-dependent protein kinase (PKA) signaling pathway is crucial to maintaining healthy energy metabolism, and mutations in PKA-linked genes represent the most common cause of monogenic obesity. Methods: For this study, we performed targeted exome sequencing of 53 PKA signaling-related genes to identify variants in genomic DNA from a large, ethnically diverse cohort of obese or metabolically challenged youth. Results: We confirmed 49 high-frequency variants, including a novel variant in the PDE11A gene (c.152C>T). Several other variants were associated with metabolic characteristics within ethnic groups. Discussion: We conclude that a PKA pathway-specific variant search led to the identification of several new genetic associations with obesity in an ethnically diverse population.
Subject(s)
Diabetes Mellitus, Type 2 , Pediatric Obesity , Adult , Adolescent , Humans , Child , Pediatric Obesity/genetics , Genome-Wide Association Study , MutationABSTRACT
BACKGROUND: Improvement of psychosocial-spiritual well-being in patients with life-threatening or life-limiting illness is desirable. Resilience and mindfulness are considered to be helpful for enhancing psychosocial-spiritual well-being. Mindfulness-based interventions have been shown to promote resilience to stress and enhance well-being. However, in medical patients, evidence for the associations between mindfulness and resilience is lacking. We hypothesize patients with higher levels of psychosocial-spiritual well-being demonstrate greater resilience and mindfulness. METHODS: 200 patients (mean age = 50.2, SD = 15.5) with serious and or life-limiting illnesses were recruited from the NIH Clinical Center. Patients completed a demographic questionnaire, the NIH-HEALS measure of psychosocial-spiritual well-being, the Connor-Davidson Resilience Scale (CD-RISC-10), and the Mindful Attention Awareness Scale (MAAS). The demographic questionnaire also included a question on current stress level. RESULTS: The NIH-HEALS was positively correlated to CD-RISC-10 (rs=0.44, p < 0.001) and MAAS (rs=0.32, p < 0.001). These findings were consistent across all three NIH-HEALS factors. Additionally, CD-RISC-10 and MAAS demonstrated a meaningful relationship to each other (rs=0.46, p < 0.001). All three constructs were inversely related to current stress level. CONCLUSIONS: Findings suggest that there is a meaningful relationship between psychosocial-spiritual well-being, mindfulness, and resilience. Mindfulness and resilience are positively correlated in a medical population. Clinical interventions aimed at enhancing psychosocial-spiritual well-being through mindfulness and resilience can be highly promising for patients with severe and or life limiting illness.
Subject(s)
Mindfulness , Humans , Middle Aged , PatientsABSTRACT
PURPOSE: Niemann-Pick disease type C1 (NPC1) is a neurodegenerative lysosomal disorder caused by pathogenic variants in NPC1. Disease progression is monitored using the NPC Neurological Severity Scale, but there are currently no established validated or qualified biomarkers. Neurofilament light chain (NfL) is being investigated as a biomarker in multiple neurodegenerative diseases. METHODS: Cross-sectional and longitudinal cerebrospinal fluid (CSF) samples were obtained from 116 individuals with NPC1. NfL levels were measured using a solid-phase sandwich enzyme-linked immunosorbent assay and compared with age-appropriate non-NPC1 comparison samples. RESULTS: Median levels of NfL were elevated at baseline (1152 [680-1840] pg/mL) in NPC1 compared with controls (167 [82-372] pg/mL; P < .001). Elevated NfL levels were associated with more severe disease as assessed by both the 17-domain and 5-domain NPC Neurological Severity Score. Associations were also observed with ambulation, fine motor, speech, and swallowing scores. Although treatment with the investigational drug 2-hydroxypropyl-ß-cyclodextrin (adrabetadex) did not decrease CSF NfL levels, miglustat therapy over time was associated with a decrease (odds ratio = 0.77, 95% CI = 0.62-0.96). CONCLUSION: CSF NfL levels are increased in individuals with NPC1, associated with clinical disease severity, and decreased with miglustat therapy. These data suggest that NfL is a biomarker that may have utility in future therapeutic trials.
Subject(s)
Niemann-Pick Disease, Type A , Niemann-Pick Disease, Type C , Humans , Intermediate Filaments/pathology , Cross-Sectional Studies , Niemann-Pick Disease, Type C/drug therapy , Niemann-Pick Disease, Type C/genetics , Niemann-Pick Disease, Type C/cerebrospinal fluid , 2-Hydroxypropyl-beta-cyclodextrin/therapeutic use , BiomarkersABSTRACT
OBJECTIVES: To analyze the frequency and rates of community respiratory virus infections detected in patients at the National Institutes of Health Clinical Center (NIHCC) between January 2015 and March 2021, comparing the trends before and during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: We conducted a retrospective study comparing frequency and rates of community respiratory viruses detected in NIHCC patients between January 2015 and March 2021. Test results from nasopharyngeal swabs and washes, bronchoalveolar lavages, and bronchial washes were included in this study. Results from viral-challenge studies and repeated positives were excluded. A quantitative data analysis was completed using cross tabulations. Comparisons were performed using mixed models, applying the Dunnett correction for multiplicity. RESULTS: Frequency of all respiratory pathogens declined from an annual range of 0.88%-1.97% between January 2015 and March 2020 to 0.29% between April 2020 and March 2021. Individual viral pathogens declined sharply in frequency during the same period, with no cases of influenza A/B orparainfluenza and 1 case of respiratory syncytial virus (RSV). Rhino/enterovirusdetection continued, but with a substantially lower frequency of 4.27% between April 2020 and March 2021, compared with an annual range of 8.65%-18.28% between January 2015 and March 2020. CONCLUSIONS: The decrease in viral respiratory infections detected in NIHCC patients during the pandemic was likely due to the layered COVID-19 prevention and mitigation measures implemented in the community and the hospital. Hospitals should consider continuing the use of nonpharmaceutical interventions in the future to prevent nosocomial transmission of respiratory viruses during times of high community viral load.
Subject(s)
COVID-19 , Influenza, Human , Respiratory Tract Infections , Viruses , Humans , COVID-19/diagnosis , COVID-19/epidemiology , Respiratory Tract Infections/diagnosis , Respiratory Tract Infections/epidemiology , Pandemics , Retrospective Studies , Influenza, Human/epidemiologyABSTRACT
BACKGROUND: While psychedelics have been shown to improve psycho-spiritual well-being, the underlying elements of this change are not well-characterized. The NIH-HEALS posits that psycho-social-spiritual change occurs through the factors of Connection, Reflection & Introspection, and Trust & Acceptance. This study aimed to evaluate the changes in NIH-HEALS scores in a cancer population with major depressive disorder undergoing psilocybin-assisted therapy. METHODS: In this Phase II, single-center, open label trial, 30 cancer patients with major depressive disorder received a fixed dose of 25 mg of psilocybin. Participants underwent group preparation sessions, simultaneous psilocybin treatment administered in adjacent rooms, and group integration sessions, along with individual care. The NIH-HEALS, a self-administered, 35-item measure of psycho-social spiritual healing was completed at baseline and post-treatment at day 1, week 1, week 3, and week 8 following psilocybin therapy. RESULTS: NIH-HEALS scores, representing psycho-social-spiritual wellbeing, improved in response to psilocybin treatment (p < 0.001). All three factors of the NIH-HEALS (Connection, Reflection & Introspection, and Trust & Acceptance) demonstrated positive change by 12.7 %, 7.7 %, and 22.4 %, respectively. These effects were apparent at all study time points and were sustained up to the last study interval at 8 weeks (p < 0.001). LIMITATIONS: The study lacks a control group, relies on a self-report measure, and uses a relatively small sample size with limited diversity that restricts generalizability. CONCLUSIONS: Findings suggest that psilocybin-assisted therapy facilitates psycho-social-spiritual growth as measured by the NIH-HEALS and its three factors. This supports the factors of Connection, Reflection & Introspection, and Trust & Acceptance as underlying elements for psycho-social-spiritual healing in cancer patients, and validates the use of the NIH-HEALS within psychedelic research.
Subject(s)
Depressive Disorder, Major , Hallucinogens , Neoplasms , Humans , Psilocybin/pharmacology , Psilocybin/therapeutic use , Depressive Disorder, Major/drug therapy , Hallucinogens/pharmacology , Hallucinogens/therapeutic use , Self Report , Neoplasms/drug therapyABSTRACT
BACKGROUND: The Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being Scale (FACIT-Sp) is a widely used measure of spiritual wellbeing. However, consensus on the best factor structure for this measure has not been reached. Both a 2-factor (Meaning/Peace, Faith) and a 3-factor (Meaning, Peace, Faith) structure are reported in the literature. In this study, we examined the factorial structure of the FACIT-Sp in a population of patients with severe and/or life-limiting medical illnesses. METHODS: The present study is a part of a larger study that validated the National Institute of Health-Healing Experiences of All Life Stressors (NIH-HEALS), a measure of psycho-social-spiritual healing developed by the Pain and Palliative Care Service at the National Institutes of Health Clinical Center (NIH-CC). The sample included 200 subjects who were recruited from the NIH Clinical Center inpatient units and outpatient clinics with severe and/or life limiting illnesses (cancer, non-genetic conditions, genetic conditions, blood dyscrasias). FACIT-Sp is a 12-item questionnaire scored on a 5-point Likert scale (0 = not at all; 4 = very much). Exploratory factor analysis (EFA) and principal component analysis (PCA) were used to analyze results and to identify the number of latent constructs and underlying factor structure. RESULTS: The results supported the 3-factor (Meaning, Peace, and Faith) model of the FACIT-Sp and accounted for the most variability (74.20%), followed by the 2-factor solution (64.95%). The identified factors related to Faith, Peace, and Meaning and were consistent with previously reported 3-factor model. CONCLUSIONS: This study confirmed the 3-factor structure of FACIT-Sp. This information can inform interventions aimed at improving quality of life and spiritual wellbeing in clinical and palliative care settings.
Subject(s)
Neoplasms , Quality of Life , Humans , Spirituality , Psychometrics/methods , Factor Analysis, Statistical , Surveys and QuestionnairesABSTRACT
BACKGROUND: Niemann-Pick disease type C1 (NPC1) is a rare autosomal recessive disease characterized by endolysosomal accumulation of unesterified cholesterol with progressive deterioration in swallowing, often leading to premature death. Although documented, the natural history of NPC1 swallowing dysfunction has yet to be delineated systematically. This manuscript aims to provide a comprehensive characterization of the phenotypic spectrum and progression of swallowing dysfunction in NPC1. METHODOLOGY: The National Institutes of Health (NIH) NPC1 natural history study (NCT00344331) enrolled 120 patients, who underwent comprehensive interpretative swallow assessments for swallowing safety, dietary modifications, and aspiration risk. Longitudinal statistical modeling accounted for all outcomes with NPC1 disease covariates (first symptom onset, age at neurological symptom onset, seizure history, duration of neurological symptoms) as well as miglustat use (a glucosylceramide synthase inhibitor) and NIH study duration (NIHSD; the length of time an individual participated in the NIH study). Probabilities for disease progression and time to swallowing decline were conducted for the entire cohort. RESULTS: Time to swallowing decline with American Speech-Language-Hearing Association National Outcome Measure (ASHA-NOMS) and the NIH-adapted Penetration Aspiration Scale (NIH-PAS) were identified: [Formula: see text] person-years and [Formula: see text] person-years, respectively. NIHSD and seizure history consistently and significantly were associated with decline (ORNIHSD = 1.34-2.10, 95% CI 1.04-3.4, p = 0.001-0.026; ORSeizure = 3.26-18.22, 1.03-167.79; p = 0.001-0.046), while miglustat use revealed protection (ORMiglustat = 0.01-0.43, 0.007-0.98; p = 0.001-0.044). The probability of decline with NPC1 neurological severity scale and annual severity increment scale were established with the aforementioned covariates, varying amongst subgroups. CONCLUSION: This study represents the most extensive collection of prospective, instrumental swallowing assessments in NPC1 to date with an interpretive analysis providing an improved understanding of NPC1 disease progression with swallowing function-serving as a foundation for clinical management and future NPC1 therapeutics.
Subject(s)
Niemann-Pick Disease, Type A , Niemann-Pick Disease, Type C , Deglutition , Disease Progression , Humans , Niemann-Pick C1 Protein , Niemann-Pick Disease, Type C/metabolism , Prospective Studies , SeizuresABSTRACT
Fibrous dysplasia (FD) is a rare mosaic disorder resulting in fractures, pain, and disability. Bone lesions appear during childhood and expand during skeletal growth. The rate at which FD lesions progress and the biochemical determinants of FD lesion formation have not been established, making it difficult to investigate and implement preventative therapies. The purpose of this study was to characterize FD lesion progression in children, and to identify clinical variables associated with progressive disease. Clinical data and imaging from an ongoing natural history study at the National Institutes of Health (NIH) were reviewed. 99m-Technetium methylene diphosphonate (99Tc-MDP) scans were used to determine Skeletal Burden Score (SBS), a validated quantitative scoring system. FD progression rate was determined by the change in the SBS in each patient per year. Thirty-one children had serial 99Tc-MDP scans, with a median age at first scan of 6 years (interquartile range [IQR] 4-8, range 2-10), and median follow-up 1.1 years (IQR 1.1-2.1, range 0.7-11.2). The median FD progression rate for the total group was 2.12 SBS units/year (IQR 0.81-2.94, range 0.05-7.81). FD progression rates were highest in children under age 8 years and declined with age (p = 0.03). Baseline disease severity was associated with subsequent disease progression (p = 0.009), with the highest FD progression rates in patients with moderate disease (baseline SBS 16-30), and lowest progression rates in those with severe disease (SBS ≥50). Serum levels of the bone formation marker osteocalcin were positively correlated with subsequent FD progression rate (p = 0.01, R = 0.58). There was no association between FD progression and baseline endocrinopathies, fractures, or surgery rates. FD lesions progress during childhood, particularly in younger children and those with moderate involvement. Osteocalcin may potentially serve as a biomarker for progressive disease. These findings may allow clinicians to investigate preventative therapies, and to identify children with FD who are candidates for early interventions. Published 2022. This article is a U.S. Government work and is in the public domain in the USA.
Subject(s)
Fibrous Dysplasia of Bone , Biomarkers , Child , Fibrous Dysplasia of Bone/diagnostic imaging , Fibrous Dysplasia of Bone/pathology , Humans , Osteocalcin , Radionuclide Imaging , Technetium Tc 99m MedronateABSTRACT
Context: Arginine-vasopressin and CRH act synergistically to stimulate secretion of ACTH. There is evidence that glucocorticoids act via negative feedback to suppress arginine-vasopressin secretion. Objective: Our hypothesis was that a postoperative increase in plasma copeptin may serve as a marker of remission of Cushing disease (CD). Design: Plasma copeptin was obtained in patients with CD before and daily on postoperative days 1 through 8 after transsphenoidal surgery. Peak postoperative copeptin levels and Δcopeptin values were compared among those in remission vs no remission. Results: Forty-four patients (64% female, aged 7-55 years) were included, and 19 developed neither diabetes insipidus (DI) or syndrome of inappropriate anti-diuresis (SIADH). Thirty-three had follow-up at least 3 months postoperatively. There was no difference in peak postoperative copeptin in remission (6.1 pmol/L [4.3-12.1]) vs no remission (7.3 pmol/L [5.4-8.4], Pâ =â 0.88). Excluding those who developed DI or SIADH, there was no difference in peak postoperative copeptin in remission (10.2 pmol/L [6.9-21.0]) vs no remission (5.4 pmol/L [4.6-7.3], Pâ =â 0.20). However, a higher peak postoperative copeptin level was found in those in remission (14.6 pmol/L [±10.9] vs 5.8 (±1.4), Pâ =â 0.03]) with parametric testing. There was no difference in the Δcopeptin by remission status. Conclusions: A difference in peak postoperative plasma copeptin as an early marker to predict remission of CD was not consistently present, although the data point to the need for a larger sample size to further evaluate this. However, the utility of this test may be limited to those who develop neither DI nor SIADH postoperatively.
ABSTRACT
BACKGROUND: Community health centers (CHCs) provide comprehensive primary and preventive care to medically underserved, low-income, and racially/ethnically diverse populations. CHCs also offer enabling services, non-clinical assistance to reduce barriers to healthcare due to unmet social and material needs, to improve access to healthcare and reduce health disparities. For patients with modifiable cardiometabolic risk factors, including obesity, hypertension, and diabetes, enabling services may provide additional support to improve disease management. However, little is known about the relationship between enabling services and healthcare accessibility and utilization among patients with cardiometabolic risk factors. METHODS: This study uses data from the 2014 Health Center Patient Survey to examine the relationship between enabling services use and delayed/foregone care, routine check-ups, and emergency room visits, among adult community health center patients in the United States with cardiometabolic risk factors (N = 2358). Outcomes of enabling services users were compared to nonusers using doubly robust propensity score matching methods and generalized linear regression models. RESULTS: Overall, enabling service users were 15.4 percentage points less likely to report delayed/foregone care and 29.4 percentage points more likely to report routine check-ups than nonusers. Enabling service users who lived in urban areas, younger and middle-aged adults, and those with two cardiometabolic risk factors were also less likely to report delayed/foregone care and/or more likely to report routine check-ups in comparison with nonusers. However, among adults with three or more cardiometabolic risk factors, enabling services use was associated with a 41.3 percentage point increase in emergency room visits and a 7.6 percentage point decrease in routine check-ups. CONCLUSIONS: The findings highlight the value in utilizing enabling services to improve timeliness and receipt of care among CHC patients with heightened cardiometabolic risk. There is a need for targeting high-risk populations with additional enabling services to support management of multiple chronic conditions.
Subject(s)
Cardiovascular Diseases , Health Services Accessibility , Adult , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/prevention & control , Community Health Centers , Health Surveys , Humans , Middle Aged , Poverty , United States/epidemiologyABSTRACT
PURPOSE: We examined abnormal pituitary imaging (API) and associated endocrine dysfunction in subjects with ECD. METHODS: A cross-sectional descriptive examination of a natural history cohort study diagnosed with ECD was conducted at a clinical research center. Subjects underwent baseline endocrine tests of anterior and posterior pituitary function and dedicated pituitary gland MRI scans. We determined the frequency of various pituitary imaging abnormalities in ECD and assessed its relationships with age, sex, body mass index (BMI), BRAF V600E status, high sensitivity C-reactive protein (hsCRP), erythrocyte sedimentation rate (ESR), pituitary hormone deficits and number, diabetes insipidus (DI), and panhypopituitarism. RESULTS: Our cohort included 61 subjects with ECD [age (SD): 54.3 (10.9) y, 46 males/15 females]. API was present in 47.5% (29/61) of ECD subjects. Loss of the posterior pituitary bright spot (36.1%) followed by thickened pituitary stalk (24.6%), abnormal enhancement (18.0%), and pituitary atrophy (14.8%) were the most common abnormalities. DI and panhypopituitarism were more frequent in subjects with API without differences in age, sex distribution, hsCRP, ESR, and BRAF V600E status compared to normal pituitary imaging. CONCLUSIONS: We noted a high burden of API and endocrinopathies in ECD. API was highly associated with the presence of panhypopituitarism and DI. Therefore, a thorough assessment of hypothalamic-pituitary integrity should be considered in subjects with ECD.