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Case Presentation: A 22-year-old male with a history of anti-neutrophil cytoplasmic antibody vasculitis, renal transplant, hypertension, and no known family history of sudden cardiac death suffered a witnessed cardiac arrest. An initial rhythm strip recorded by emergency medical services revealed ventricular fibrillation. Return of spontaneous circulation was achieved after three rounds of cardiopulmonary resuscitation, defibrillation, and intravenous epinephrine. The patient was brought to the emergency department and admitted to the intensive care unit. He was diagnosed with Brugada syndrome, and an automatic implantable cardioverter-defibrillator (AICD) was placed after discharge. Discussion: Brugada syndrome is characterized electrocardiographically by ≥2 millimeters (mm) ST-segment elevation in leads V1-V2 with either "coved type" (type 1) or "saddleback" (type 2) ST-segment morphology, or ≤2 mm ST-segment elevation in V1-V2 with either "coved" or "saddleback" morphology (type 3). The absence of these patterns on isolated electrocardiograms (ECG) does not exclude the diagnosis, as dynamic fluctuations in ECG patterns are well-documented and can be induced by various physiologic stressors. This case provides an uncommon, complete electrocardiographic history of Brugada syndrome, from out-of-hospital cardiac arrest to AICD placement and depicts dynamic fluctuations between Brugada patterns and normal ECGs. This highlights the importance of serial ECGs in diagnosis, as sudden cardiac death is often the first or only presentation of Brugada syndrome.
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BACKGROUND: A recent National Institute on Drug Addiction Call to Action focused on expanding methadone treatment access for individuals with opioid use disorder (OUD). One research priority identified was optimal educational and support structures, including training to provide methadone across multiple healthcare settings (e.g., primary care, opioid treatment programs [OTPs], pharmacies) and healthcare workers (HCWs) (e.g., providers, pharmacists). This scoping review sought to better understand HCWs' knowledge, attitudes, and stigma as it relates to methadone provision. METHODS: Four databases (PubMed, PsycInfo, CINAHL, Web of Science) were searched for publications between 2010 and 2022 using keywords-methadone, HCW, outpatient setting, knowledge, attitudes, and stigma, focusing on HCWs in general and pharmacists specifically. RESULTS: A total of 2,747 articles were identified and 14 met inclusion criteria for review. Settings included OTPs (n = 4), specialty addiction treatment clinics (n = 3), community pharmacies (n = 2), and multiple settings (n = 5). All articles (n = 14) examined methadone-related attitudes. Despite approval of methadone in 1972 to treat OUD, four articles illustrated continued methadone-related stigma held by HCWs. In response to COVID-19-related policy changes allowing methadone take-home flexibility, OTP clinicians expressed a range of attitudes concerning patient risk and potential program liability around diversion and misuse. One article assessing knowledge suggested that, even when most pharmacists correctly answered knowledge questions, a significant minority had misunderstandings that could undermine effective treatment. CONCLUSIONS: Given the current imbalance between methadone treatment demand and availability, there is a critical need to expand outpatient methadone services. Pharmacists partnering with OTPs represent a logical but underutilized access point. We identified key areas to improve HCWs methadone-related knowledge, attitudes, and stigma. Future research should explore the impact of outpatient pharmacy-OTP and other expansion services, and systematic training, education, and evaluation of methadone-related understanding, including assessment tools to measure knowledge, attitudes, and stigma.
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ABSTRACT: Although survivors of childhood cancer are at an increased risk, little is known about the prevalence of chronic pain, associated interference, and daily pain experiences. Survivors (N = 233; mean age = 40.8 years, range 22-64 years; mean time since diagnosis = 32.7 years) from the Childhood Cancer Survivor Study completed pain and psychosocial measures. Survivors with chronic pain completed 2-week, daily measures assessing pain and psychological symptoms using mHealth-based ecological momentary assessment. Multivariable-modified Poisson and linear regression models estimated prevalence ratio estimates (PR) and mean effects with 95% confidence intervals (CI) for associations of key risk factors with chronic pain and pain interference, respectively. Multilevel mixed models examined outcomes of daily pain and pain interference with prior day symptoms. Ninety-six survivors (41%) reported chronic pain, of whom 23 (24%) had severe interference. Chronic pain was associated with previous intravenous methotrexate treatment (PR = 1.6, 95% CI 1.1-2.3), respiratory (PR = 1.8, 95% CI 1.2-2.5), gastrointestinal (PR = 1.6, 95% CI 11.0-2.3), and neurological (PR = 1.5, 95% CI 1.0-2.1) chronic health conditions, unemployment (PR = 1.4, 95% CI 1.0-1.9) and clinically significant depression and anxiety (PR = 2.9, 95% CI 2.0-4.2), as well as a diagnosis of childhood Ewing sarcoma or osteosarcoma (PR = 1.9, 95% CI 1.0-3.5). Higher pain interference was associated with cardiovascular and neurological conditions, unemployment and clinical levels of depression and/or anxiety, and fear of cancer recurrence. For male, but not female survivors, low sleep quality, elevated anxiety, and elevated depression predicted high pain intensity and interference the next day. A substantial proportion of childhood cancer survivors experience chronic pain and significant associated interference. Chronic pain should be routinely evaluated, and interventions are needed.
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Importance: Approximately 1% to 3% of gastric cancers and 5% of lobular breast cancers are hereditary. Loss of function CDH1 gene variants are the most common gene variants associated with hereditary diffuse gastric cancer and lobular breast cancer. Previously, the lifetime risk of gastric cancer was estimated to be approximately 25% to 83% and for breast cancer it was estimated to be approximately 39% to 55% in individuals with loss of function CDH1 gene variants. Objective: To describe gastric and breast cancer risk estimates for individuals with CDH1 variants. Design, Setting, and Participants: Multicenter, retrospective cohort and modeling study of 213 families from North America with a CDH1 pathogenic or likely pathogenic (P/LP) variant in 1 or more family members conducted between January 2021 and August 2022. Main Outcomes and Measures: Hazard ratios (HRs), defined as risk in variant carriers relative to noncarriers, were estimated for each cancer type and used to calculate cumulative risks and risks per decade of life up to age 80 years. Results: A total of 7323 individuals from 213 families were studied, including 883 with a CDH1 P/LP variant (median proband age, 53 years [IQR, 42-62]; 4% Asian; 4% Hispanic; 85% non-Hispanic White; 50% female). In individuals with a CDH1 P/LP variant, the prevalence of gastric cancer was 13.9% (123/883) and the prevalence of breast cancer among female carriers was 26.3% (144/547). The estimated HR for advanced gastric cancer was 33.5 (95% CI, 9.8-112) at age 30 years and 3.5 (95% CI, 0.4-30.3) at age 70 years. The lifetime cumulative risk of advanced gastric cancer in male and female carriers was 10.3% (95% CI, 6%-23.6%) and 6.5% (95% CI, 3.8%-15.1%), respectively. Gastric cancer risk estimates based on family history indicated that a carrier with 3 affected first-degree relatives had a penetrance of approximately 38% (95% CI, 25%-64%). The HR for breast cancer among female carriers was 5.7 (95% CI, 2.5-13.2) at age 30 years and 3.9 (95% CI, 1.1-13.7) at age 70 years. The lifetime cumulative risk of breast cancer among female carriers was 36.8% (95% CI, 25.7%-62.9%). Conclusions and Relevance: Among families from North America with germline CDH1 P/LP variants, the cumulative risk of gastric cancer was 7% to 10%, which was lower than previously described, and the cumulative risk of breast cancer among female carriers was 37%, which was similar to prior estimates. These findings inform current management of individuals with germline CDH1 variants.
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BACKGROUND AND HYPOTHESIS: Up to 43% of people with schizophrenia have a lifetime cannabis use disorder (CUD). Tetrahydrocannabinol (THC) has been shown to exacerbate psychosis in a dose-dependent manner, but little research has assessed its effects on schizophrenia and co-occurring CUD (SCZ-CUD). In this double-dummy, placebo-controlled trial (total nâ =â 130), we hypothesized that a modest dose of THC would worsen cognitive function but not psychosis. STUDY DESIGN: Effects of single-dose oral THC (15 mg dronabinol) or smoked 3.5% THC cigarettes vs placebo in SCZ-CUD or CUD-only on positive and negative symptoms of schizophrenia (only for SCZ-CUD), cognition, and drug experiences assessed several hours after drug administration. SCZ-only and healthy control participants were also assessed. STUDY RESULTS: Drug liking was higher in THC groups vs placebo. Neither smoked THC nor oral dronabinol predicted positive or negative symptom subscale scores 2 and 5 h, respectively, after drug exposure in SCZ-CUD participants. The oral dronabinol SCZ-CUD group, but not smoked THC SCZ-CUD group, performed worse than placebo on verbal learning (Bâ =â -9.89; 95% CI: -16.06, -3.18; Pâ =â .004) and attention (Bâ =â -0.61; 95% CI: -1.00, -0.23; Pâ =â .002). Every 10-point increment in serum THCâ +â THCC ng/ml was associated with increased negative symptoms (0.40 points; 95% CI: 0.15, 0.65; Pâ =â .001; subscale ranges 7-49) and trends were observed for worse positive symptoms and performance in verbal learning, delayed recall, and working memory. CONCLUSIONS: In people with SCZ-CUD, a modest single dose of oral THC was associated with worse cognitive functioning without symptom exacerbation several hours after administration, and a THC dose-response effect was seen for negative symptoms.
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BACKGROUND: Influenza vaccine uptake is low among underserved populations whose primary health care access occurs in emergency departments. We sought to determine whether implementation of two interventions would increase 30-day influenza vaccine uptake in unvaccinated patients in the emergency department. METHODS: This three-group, prospective, cluster-randomized controlled trial compared two interventions with a control group in noncritically ill, adult patients in the emergency department who were not vaccinated for influenza in the current vaccine season. The unit of randomization was individual calendar days. Participants received either Intervention M (an influenza vaccine messaging platform consisting of a video, one-page flyer, and scripted message, followed by a vaccine acceptance question and provider notification if participants indicated vaccine acceptance), Intervention Q (no messaging but the vaccine acceptance question and provider notification), or control (usual care/no intervention). The primary outcome was receipt of an influenza vaccine at 30 days ascertained by electronic health record review and telephone follow-up, comparing the Intervention M group with the control group. Secondary outcomes included comparisons of 30-day vaccine uptake in Intervention Q versus control and Intervention M versus Intervention Q. RESULTS: Between October 2022 and February 2023, a total of 767 trial participants were enrolled at six emergency departments in five U.S. cities. Median age was 46 years; 353 (46%) participants were female, 274 (36%) were African American, and 158 (21%) were Latinx; 126 (16%) lacked health insurance, and 244 (32%) lacked primary care. The Intervention M, Intervention Q, and control groups had 30-day vaccine uptakes of 41%, 32%, and 15%, respectively (P<0.0001 for Intervention M vs. control). Comparing Intervention M versus Intervention Q, the adjusted difference in 30-day vaccine uptake was 8.7 percentage points (95% confidence interval, -0.1 to 17.6 percentage points). CONCLUSIONS: Implementation of influenza vaccine messaging platforms (video clips, printed materials, and verbal scripts) improved 30-day vaccine uptake among unvaccinated patients in the emergency department. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT05836818.).
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Servicio de Urgencia en Hospital , Vacunas contra la Influenza , Gripe Humana , Humanos , Servicio de Urgencia en Hospital/estadística & datos numéricos , Masculino , Femenino , Vacunas contra la Influenza/administración & dosificación , Persona de Mediana Edad , Gripe Humana/prevención & control , Adulto , Estudios Prospectivos , Vacunación/estadística & datos numéricos , Anciano , Promoción de la Salud/métodos , Aceptación de la Atención de Salud/estadística & datos numéricosRESUMEN
OBJECTIVES: To determine the predictive value of social determinants of health (SDoH) variables on 30-day readmission following a sepsis hospitalization as compared with traditional clinical variables. DESIGN: Multicenter retrospective cohort study using patient-level data, including demographic, clinical, and survey data. SETTINGS: Thirty-five hospitals across the United States from 2017 to 2021. PATIENTS: Two hundred seventy-one thousand four hundred twenty-eight individuals in the AllofUs initiative, of which 8909 had an index sepsis hospitalization. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Unplanned 30-day readmission to the hospital. Multinomial logistic regression models were constructed to account for survival in determination of variables associate with 30-day readmission and are presented as adjusted odds rations (aORs). Of the 8909 sepsis patients in our cohort, 21% had an unplanned hospital readmission within 30 days. Median age (interquartile range) was 54 years (41-65 yr), 4762 (53.4%) were female, and there were self-reported 1612 (18.09%) Black, 2271 (25.49%) Hispanic, and 4642 (52.1%) White individuals. In multinomial logistic regression models accounting for survival, we identified that change to nonphysician provider type due to economic reasons (aOR, 2.55 [2.35-2.74]), delay of receiving medical care due to lack of transportation (aOR, 1.68 [1.62-1.74]), and inability to afford flow-up care (aOR, 1.59 [1.52-1.66]) were strongly and independently associated with a 30-day readmission when adjusting for survival. Patients who lived in a ZIP code with a high percentage of patients in poverty and without health insurance were also more likely to be readmitted within 30 days (aOR, 1.26 [1.22-1.29] and aOR, 1.28 [1.26-1.29], respectively). Finally, we found that having a primary care provider and health insurance were associated with low odds of an unplanned 30-day readmission. CONCLUSIONS: In this multicenter retrospective cohort, several SDoH variables were strongly associated with unplanned 30-day readmission. Models predicting readmission following sepsis hospitalization may benefit from the addition of SDoH factors to traditional clinical variables.
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Readmisión del Paciente , Sepsis , Determinantes Sociales de la Salud , Humanos , Readmisión del Paciente/estadística & datos numéricos , Femenino , Masculino , Estudios Retrospectivos , Persona de Mediana Edad , Sepsis/mortalidad , Sepsis/terapia , Anciano , Adulto , Estados Unidos/epidemiología , Modelos Logísticos , Factores de Riesgo , Estudios de CohortesRESUMEN
The N-methyl-D-aspartate (NMDA) receptor is a glutamate-activated cation channel that is critical to many processes in the brain. Genome-wide association studies suggest that glutamatergic neurotransmission and NMDA receptor-mediated synaptic plasticity are important for body weight homeostasis1. Here we report the engineering and preclinical development of a bimodal molecule that integrates NMDA receptor antagonism with glucagon-like peptide-1 (GLP-1) receptor agonism to effectively reverse obesity, hyperglycaemia and dyslipidaemia in rodent models of metabolic disease. GLP-1-directed delivery of the NMDA receptor antagonist MK-801 affects neuroplasticity in the hypothalamus and brainstem. Importantly, targeting of MK-801 to GLP-1 receptor-expressing brain regions circumvents adverse physiological and behavioural effects associated with MK-801 monotherapy. In summary, our approach demonstrates the feasibility of using peptide-mediated targeting to achieve cell-specific ionotropic receptor modulation and highlights the therapeutic potential of unimolecular mixed GLP-1 receptor agonism and NMDA receptor antagonism for safe and effective obesity treatment.
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Maleato de Dizocilpina , Péptido 1 Similar al Glucagón , Receptor del Péptido 1 Similar al Glucagón , Obesidad , Receptores de N-Metil-D-Aspartato , Animales , Humanos , Masculino , Ratones , Ratas , Tronco Encefálico/metabolismo , Tronco Encefálico/efectos de los fármacos , Modelos Animales de Enfermedad , Maleato de Dizocilpina/efectos adversos , Maleato de Dizocilpina/farmacología , Maleato de Dizocilpina/uso terapéutico , Dislipidemias/tratamiento farmacológico , Dislipidemias/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Hiperglucemia/tratamiento farmacológico , Hiperglucemia/metabolismo , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Ratones Endogámicos C57BL , Plasticidad Neuronal/efectos de los fármacos , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Ratas Sprague-Dawley , Ratas Wistar , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidoresRESUMEN
Introduction: The incidence of sexually transmitted infections (STI) increased in the United States between 2017-2021. There is limited data describing STI co-testing practices and the prevalence of STI co-infections in emergency departments (ED). In this study, we aimed to describe the prevalence of co-testing and co-infection of HIV, hepatitis C virus (HCV), syphilis, gonorrhea, and chlamydia, in a large, academic ED. Methods: This was a single-center, retrospective cross-sectional study of ED patients tested for HIV, HCV, syphilis, gonorrhea or chlamydia between November 27, 2018-May 26, 2019. In 2018, the study institution implemented an ED-based infectious diseases screening program in which any patient being tested for gonorrhea/chlamydia was eligible for opt-out syphilis screening, and any patient 18-64 years who was having blood drawn for any clinical purpose was eligible for opt-out HIV and HCV screening. We analyzed data from all ED patients ≥13 years who had undergone STI testing. The outcomes of interest included prevalence of STI testing/co-testing and the prevalence of STI infection/co-infection. We describe data with simple descriptive statistics. Results: During the study period there were 30,767 ED encounters for patients ≥13 years (mean age: 43 ± 14 years, 52% female), and 7,866 (26%) were tested for at least one of HIV, HCV, syphilis, gonorrhea, or chlamydia. We observed the following testing frequencies (and prevalence of infection): HCV, 7,539 (5.0%); HIV, 7,359 (0.9%); gonorrhea, 574 (6.1%); chlamydia, 574 (9.8%); and syphilis, 420 (10.5%). Infectious etiologies with universal testing protocols (HIV and HCV) made up the majority of STI testing. In patients with syphilis, co-infection with chlamydia (21%, 9/44) and HIV (9%, 4/44) was high. In patients with gonorrhea, co-infection with chlamydia (23%, 8/35) and syphilis (9%, 3/35) was high, and in patients with chlamydia, co-infection with syphilis (16%, 9/56) and gonorrhea (14%, 8/56) was high. Patients with HCV had low co-infection proportions (<2%). Conclusion: Prevalence of STI co-testing was low among patients with clinical suspicion for STIs; however, co-infection prevalence was high in several co-infection pairings. Future efforts are needed to improve STI co-testing rates among high-risk individuals.
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Coinfección , Servicio de Urgencia en Hospital , Gonorrea , Infecciones por VIH , Hepatitis C , Tamizaje Masivo , Enfermedades de Transmisión Sexual , Sífilis , Humanos , Estudios Transversales , Femenino , Estudios Retrospectivos , Adulto , Masculino , Enfermedades de Transmisión Sexual/diagnóstico , Enfermedades de Transmisión Sexual/epidemiología , Coinfección/epidemiología , Coinfección/diagnóstico , Gonorrea/diagnóstico , Gonorrea/epidemiología , Sífilis/diagnóstico , Sífilis/epidemiología , Prevalencia , Persona de Mediana Edad , Hepatitis C/epidemiología , Hepatitis C/diagnóstico , Tamizaje Masivo/métodos , Infecciones por VIH/epidemiología , Infecciones por VIH/diagnóstico , Infecciones por Chlamydia/diagnóstico , Infecciones por Chlamydia/epidemiología , Adolescente , Adulto JovenRESUMEN
BACKGROUND: Pharmacy-based screening and brief interventions (SBI) offer opportunities to identify opioid misuse and opioid safety risks and provide brief interventions that do not overly burden pharmacists. Currently, such interventions are being developed without patient input and in-depth contextual data and insufficient translation into practice. The purpose of this study is to qualitatively explore and compare patient and pharmacist perceptions and needs regarding a pharmacy-based opioid misuse SBI and to identify relevant SBI features and future implementation strategies. METHODS: Using the Consolidated Framework for Implementation Research, we conducted semi-structured interviews with 8 patients and 11 pharmacists, to explore needs and barriers to participating in a pharmacy-based SBI. We recruited a purposive sample of English-speaking patients prescribed opioids for chronic or acute pain and pharmacists practicing in varied pharmacies (small independent, large-chain, specialty retail) settings. We used an inductive content analysis approach to analyze patient interview data. Then through a template analysis approach involving comparison of pharmacist and patient themes, we developed strategies for SBI implementation. RESULTS: Most patient participants were white, older, described living in suburban areas, and were long-term opioid users. We identified template themes related to individual, interpersonal, intervention, and implementation factors and inferred applications for SBI design or potential SBI implementation strategies. We found that patients needed education on opioid safety and general opioid use, regardless of opioid use behaviors. Pharmacists described needing patient-centered training, protocols, and scripts to provide SBI. A short-self-reported screening and brief interventions including counseling, naloxone, and involving prescribers were discussed by both groups. CONCLUSIONS: Through this implementation-focused qualitative study, we identified patient needs such as opioid safety education delivered in a private and convenient format and pharmacist needs including training, workflow integration, protocols, and a time-efficient intervention for effective pharmacy-based SBI. Alternate formats of SBI using digital health technologies may be needed for effective implementation. Our findings can be used to develop patient-centered pharmacy-based SBI that can be implemented within actual pharmacy practice.
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Servicios Comunitarios de Farmacia , Trastornos Relacionados con Opioides , Farmacias , Humanos , Analgésicos Opioides/efectos adversos , Intervención en la Crisis (Psiquiatría) , Farmacéuticos/psicología , Trastornos Relacionados con Opioides/diagnóstico , Trastornos Relacionados con Opioides/tratamiento farmacológicoRESUMEN
PURPOSE: Triple-negative breast cancer (TNBC) often metastasizes to the central nervous system (CNS) and has the highest propensity among breast cancer subtypes to develop leptomeningeal disease (LMD). LMD is a spread of cancer into leptomeningeal space that speeds up the disease progression and severely aggravates the prognosis. LMD has limited treatment options. We sought to test whether the common anti-helminthic drug mebendazole (MBZ) may be effective against murine TNBC LMD. METHODS: A small-molecule screen involving TNBC cell lines identified benzimidazoles as potential therapeutic agents for further study. In vitro migration assays were used to evaluate cell migration capacity and the effect of MBZ. For in vivo testing, CNS metastasis was introduced into BALB/c athymic nude mice through internal carotid artery injections of brain-tropic MDA-MB-231-BR or MCF7-BR cells. Tumor growth and spread was monitored by bioluminescence imaging and immunohistochemistry. MBZ was given orally at 50 and 100 mg/kg doses. MBZ bioavailability was assayed by mass spectrometry. RESULTS: Bioinformatic analysis and migration assays revealed higher migratory capacity of TNBC compared to other breast cancer subtypes. MBZ effectively slowed down migration of TNBC cell line MDA-MB-231 and its brain tropic derivative MDA-MB-231-BR. In animal studies, MBZ reduced leptomeningeal spread, and extended survival in brain metastasis model produced by MDA-MB-231-BR cells. MBZ did not have an effect in the non-migratory MCF7-BR model. CONCLUSIONS: We demonstrated that MBZ is a safe and effective oral agent in an animal model of TNBC CNS metastasis. Our findings are concordant with previous efforts involving MBZ and CNS pathology and support the drug's potential utility to slow down leptomeningeal spread.
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Movimiento Celular , Reposicionamiento de Medicamentos , Mebendazol , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias de la Mama Triple Negativas , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Animales , Humanos , Femenino , Mebendazol/farmacología , Mebendazol/uso terapéutico , Ratones , Movimiento Celular/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Línea Celular Tumoral , Neoplasias del Sistema Nervioso Central/secundario , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Proliferación Celular/efectos de los fármacosRESUMEN
Purpose: Triple-negative breast cancer (TNBC) is an aggressive subtype that often metastasizes to the brain. Leptomeningeal disease (LMD), a devastating brain metastasis common in TNBC, has limited treatment options. We sought to test whether the common anti-helminthic drug mebendazole (MBZ) may be effective against murine TNBC LMD. Methods: A small-molecule screen involving TNBC cell lines identified benzimidazoles as potential therapeutic agents for further study. In vitro migration assays were used to evaluate cell migration capacity and the effect of MBZ. For in vivo testing, LMD was introduced into BALB/c athymic nude mice through internal carotid artery injections of brain-tropic MDA-MB-231-BR or MCF7-BR cells. Tumor growth and spread was monitored by bioluminescence imaging. MBZ was given orally at 50 and 100 mg/kg doses. MBZ bioavailability was assayed by mass spectrometry. Results: Bioinformatic analysis and migration assays revealed higher migratory capacity of TNBC compared to other breast cancer subtypes. MBZ effectively slowed down migration of TNBC cell line MDA-MB-231 and its brain tropic derivative MDA-MB-231-BR. In animal studies, MBZ reduced tumor growth and extended survival in the LMD model produced by MDA-MB-231-BR cells. MBZ did not have an effect in the non-migratory MCF7-BR model. Conclusions: We demonstrated that MBZ is a safe and effective oral agent in an animal model of TNBC LMD. Our findings are concordant with previous efforts involving MBZ and central nervous system pathology and further support the drug's potential utility as an alternative therapeutic for TNBC LMD.
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INTRODUCTION: Mercaptopurine (6MP) and methotrexate (MTX) are commonly used for maintenance chemotherapy for acute lymphoblastic leukemia (ALL). These medications have been associated with various side effects such as myelosuppression, colitis, and thyroiditis in addition to numerous cutaneous adverse events. Cutaneous side-effects most reported include mucositis, alopecia, xerosis, and pruritus. We report an interesting case of hand-foot syndrome to 6MP in a child on maintenance therapy for B-cell ALL from an alteration in medication metabolism. CASE: We report a 10-year-old male on maintenance chemotherapy for pre-Bcell ALL who presented to the hospital with worsening oral lesions and erythematous, fissured plaques on the palms and soles. Maintenance therapy consisted of IV vincristine and 5-day pulse of steroids every 12 weeks, daily 6MP, and weekly MTX, which were increased to ≥ 150% of standard dosing due to persistent absolute neutrophil counts > 1500. Metabolites obtained on admission demonstrated elevated 6MMP metabolites at 35,761 (normal < 5700). TPMT and NUDT15 enzyme activity were normal and no alterations in genotyping were discovered. OUTCOME: Patient's oral chemotherapy, including both 6MP and MTX, were stopped and allopurinol 100â mg daily was initiated, which lead to overall improvement. DISCUSSION: Clinical findings of acute mucositis and worsening of hand-foot syndrome, in the setting of inadequate myelosuppression in a child on maintenance therapy for ALL should raise concerns to consider altered metabolism pathway leading to toxic metabolite buildup. Allopurinol can play in improving cutaneous manifestation and chemotherapeutic dosing in patients with altered metabolism.
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Síndrome Mano-Pie , Mercaptopurina , Metotrexato , Mucositis , Humanos , Masculino , Síndrome Mano-Pie/etiología , Niño , Metotrexato/efectos adversos , Metotrexato/uso terapéutico , Mucositis/inducido químicamente , Mercaptopurina/efectos adversos , Mercaptopurina/uso terapéutico , Mercaptopurina/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Vincristina/efectos adversos , Vincristina/uso terapéutico , Antimetabolitos Antineoplásicos/efectos adversosRESUMEN
BACKGROUND: Screening and brief interventions (SBI) can help identify opioid safety risks and healthcare professionals can accordingly intervene without a significant increase in workload. Pharmacists, one of the most accessible healthcare professionals, are uniquely positioned to offer SBI. To design an effective intervention with high potential for implementation, we explored pharmacist needs and barriers regarding SBI for opioid use disorders. METHODS: Using the Consolidated Framework for Implementation Research (CFIR), we conducted 11 semi-structured 60-minute interviews with community pharmacists. We used a purposeful sample of English-speaking pharmacists practicing in varied pharmacies (small independent, large-chain, specialty-retail) and positions (managers, owners, full-time/part-time pharmacists). Transcriptions were analyzed using deductive content analysis based on CFIR constructs, followed by inductive open coding. Utilizing a theoretical framework for data collection and analysis, a diverse sample of pharmacist roles, peer debriefing, and 2 independent coders for each transcript, altogether increased the credibility and transferability of our research. Data collection and analysis continued until data saturation was achieved. RESULTS: Pharmacists described good working relationships with colleagues, organization cultures that were open to new initiatives, and believed the SBI to be compatible with their organization goals and pharmacy structure, which are facilitators for future SBI implementation. Pharmacists were motivated by improved patient outcomes, more patient interaction and clinical roles, representing facilitators at the individual level. They also described stigma toward patients, mixed need for change, and lack of knowledge regarding SBI, which are potential barriers to be addressed. Pharmacists believed that the SBI model was adaptable, not complicated, and benefits outweighed implementation costs. CONCLUSIONS: We addressed current SBI literature gaps-mainly lack of focus on implementation and contextual data, through rigorous implementation-focused qualitative research. Our exploratory findings have direct implications on future pharmacy-based SBI implementation.
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Trastornos Relacionados con Opioides , Farmacia , Humanos , Farmacéuticos , Intervención en la Crisis (Psiquiatría) , Personal de Salud , Trastornos Relacionados con Opioides/diagnósticoRESUMEN
The WHO aims to detect 90% of global cases of hepatitis B virus (HBV) by 2030. Sub-Saharan Africa carries a disproportionate burden of HBV and hepatocellular carcinoma (HCC). In this study, we sought to assess the utility of a combined HBV and HCC screening program in Tanzania. We conducted a prospective, serial cross-sectional study of patients who participated in a combined HBV and HCC screening program at a regional referral hospital emergency department (ED) in Arusha, Tanzania, between April 19, 2022 and June 3, 2022. All patients completed a study questionnaire and were tested for HBV surface antigen. Patients who were HBV positive were screened for HCC via point-of-care ultrasound (POCUS). The primary outcome was the number of new HBV diagnoses. Data were analyzed with descriptive statistics. A total of 846 patients were tested for HBV (primary ED: 761, clinic referral: 85). The median age of patients was 44 ± 15 years, and 66% were female. Only 15% of patients reported having a primary care doctor. Thirteen percent of patients had been previously vaccinated for HBV. There were 17 new HBV diagnoses (primary ED: 16, clinic referral: 1), which corresponds to a seroprevalence of 2.0% (95% CI: 1.2%, 3.2%). No patients had liver masses detected on POCUS. An ED-based, combined HBV and HCC screening protocol can be feasibly implemented. This study could serve as a model for HBV/HCC screening in regions with high HBV endemicity and low rates of community screening.
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Carcinoma Hepatocelular , Hepatitis B , Neoplasias Hepáticas , Humanos , Femenino , Adulto , Persona de Mediana Edad , Masculino , Virus de la Hepatitis B , Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/epidemiología , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/epidemiología , Tanzanía/epidemiología , Estudios Prospectivos , Estudios Seroepidemiológicos , Estudios Transversales , Antígenos de Superficie de la Hepatitis B , Servicio de Urgencia en Hospital , Pruebas en el Punto de Atención , Hepatitis B/prevención & controlRESUMEN
Osteosarcoma (OS) is a primary malignant bone tumor characterized by frequent metastasis, rapid disease progression, and a high rate of mortality. Treatment options for OS have remained largely unchanged for decades, consisting primarily of cytotoxic chemotherapy and surgery, thus necessitating the urgent need for novel therapies. Tropolones are naturally occurring seven-membered non-benzenoid aromatic compounds that possess antiproliferative effects in a wide array of cancer cell types. MO-OH-Nap is an α-substituted tropolone that has activity as an iron chelator. Here, we demonstrate that MO-OH-Nap activates all three arms of the unfolded protein response (UPR) pathway and induces apoptosis in a panel of human OS cell lines. Co-incubation with ferric chloride or ammonium ferrous sulfate completely prevents the induction of apoptotic and UPR markers in MO-OH-Nap-treated OS cells. MO-OH-Nap upregulates transferrin receptor 1 (TFR1) protein levels, as well as TFR1, divalent metal transporter 1 (DMT1), iron-regulatory proteins (IRP1, IRP2), ferroportin (FPN), and zinc transporter 14 (ZIP14) transcript levels, demonstrating the impact of MO-OH-Nap on iron-homeostasis pathways in OS cells. Furthermore, MO-OH-Nap treatment restricts the migration and invasion of OS cells in vitro. Lastly, metabolomic profiling of MO-OH-Nap-treated OS cells revealed distinct changes in purine and pyrimidine metabolism. Collectively, we demonstrate that MO-OH-Nap-induced cytotoxic effects in OS cells are dependent on the tropolone's ability to alter cellular iron availability and that this agent exploits key metabolic pathways. These studies support further evaluation of MO-OH-Nap as a novel treatment for OS.
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Osteosarcoma , Tropolona , Humanos , Tropolona/farmacología , Hierro/metabolismo , Hierro/farmacología , Apoptosis , Línea Celular , Osteosarcoma/tratamiento farmacológico , Línea Celular TumoralRESUMEN
Although the recognition of Indigenous Peoples' contributions to climate governance by the international community has gradually increased, a rights-based approach in national climate action is still largely absent. This article analyses the recognition of Indigenous Peoples' rights in Nationally Determined Contributions (NDCs) under the Paris Agreement. We conducted a content analysis of all NDCs submitted between 2016 and May 2022. Through a five-pronged framework of sustainable self-determination, we assessed how the NDCs recognise: i. Indigenous Peoples as rights-holders; ii. Indigenous jurisdiction over land; iii. Indigenous knowledge systems; iv. Indigenous Peoples' right to full and effective participation in climate governance; and v. the legacy of colonialism. NDCs with references related to Indigenous Peoples are increasing. However, questions remain regarding their sincerity and commitment to implementation. States must therefore make more significant efforts to ensure that the NDCs take a rights-based approach and contribute to strengthening Indigenous Peoples' role and say in climate governance.
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Cambio Climático , Gobierno , Pueblos Indígenas , HumanosRESUMEN
BACKGROUND: Implementation evaluations based on a hybrid deductive-inductive approach provide a detailed understanding of organizational choices to introduce and implement complex interventions and may help explain implementation success or failure. However, such evaluations may not be feasible due to resource constraints. Qualitative analyses of artifacts collected for other purposes during implementation may represent a cost-effective method to understand program implementation when robust evaluations are not feasible. This study used a work systems evaluation of how nursing homes (NHs) implemented a urinary tract infection (UTI) recognition and management improvement toolkit. METHODS: Thirty NHs participated in a randomized control trial in which intervention NHs (n = 12) were assigned a clinical coach who employed a standard template to structure coach calls with the NH champion. A hybrid inductive-deductive approach, using the Systems Engineering Initiative for Patient Safety (SEIPS) model, characterized three action domains related to (1) engagement of staff and providers, (2) distribution of toolkit elements, and (3) toolkit use. RESULTS: A total of 369 coded segments from 148 coach notes generated by three coaches working with 18 NH champions were examined. Planned changes (n = 203) were more frequent compared to actual changes (n = 169). While most NHs quickly engaged staff and providers, which leadership appeared to support, engagement actions were hindered in some NHs due to champion instability or extended champion or medical director absences. Dissemination of materials to family and providers and distribution of tools to staff occurred quickly in 75% of NHs, although delays were encountered in some NHs, usually because of champion instability. CONCLUSIONS: Implementing NH practice change is challenging, and studies examining actions to support planned versus actual change in this setting are limited. The application of the SEIPS model to coach notes collected during the implementation of a structured behavioral intervention to improve the recognition and management of UTI in NHs generated unique insights into the work system and how staff attempted to implement changes. This study identified several factors that interfered with progression from planning to actual change. Future studies are needed to better understand how to best support change interventions in NHs. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03520010 , Registered May 9, 2018.