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BACKGROUND: Canadian health systems fare poorly in providing timely access to elective surgical care, which is crucial for quality, trust, and satisfaction. METHODS: We conducted a cross-sectional analysis of surgical wait times for adults receiving non-urgent cataract surgery, knee arthroplasty, hip arthroplasty, gallbladder surgery, and non-cancer uterine surgery in Ontario, Canada, between 2013 and 2019. We obtained data from the Wait Times Information System (WTIS) database. Inter- and intra-hospital and surgeon variations in wait time were described graphically with caterpillar plots. We used non-nested 3-level hierarchical random effects models to estimate variation partition coefficients, quantifying the proportion of wait time variance attributable to surgeons and hospitals. RESULTS: A total of 942,605 procedures at 107 healthcare facilities, conducted by 1,834 surgeons, were included in the analysis. We observed significant intra- and inter-provider variations in wait times across all five surgical procedures. Inter-facility median wait time varied between six-fold for gallbladder surgery and 15-fold for knee arthroplasty. Inter-surgeon variation was more pronounced, ranging from a 17-fold median wait time difference for cataract surgery to a 216-fold difference for non-cancer uterine surgery. The proportion of variation in wait times attributable to facilities ranged from 6.2% for gallbladder surgery to 23.0% for cataract surgery. In comparison, surgeon-related variation ranged from 16.0% for non-cancer uterine surgery to 28.0% for cataract surgery. IMPLICATIONS: There is extreme variability in surgical wait times for five common, high-volume, non-urgent surgical procedures. Strategies to address surgical wait times must address the variation between service providers through better coordination of supply and demand. Approaches such as single-entry models could improve surgical system performance.
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Procedimentos Cirúrgicos Eletivos , Cirurgiões , Listas de Espera , Humanos , Ontário , Estudos Transversais , Feminino , Cirurgiões/estatística & dados numéricos , Masculino , Procedimentos Cirúrgicos Eletivos/estatística & dados numéricos , Hospitais/estatística & dados numéricos , Adulto , Pessoa de Meia-Idade , Idoso , Fatores de TempoRESUMO
OBJECTIVES: To determine the baseline trends in the total birth prevalence of neural tube defects (NTDs) in England (2000-2019) to enable the impact of folic acid fortification of non-wholemeal wheat flour to be monitored. DESIGN: Population-based, observational study using congenital anomaly (CA) registration data for England curated by the National Congenital Anomaly and Rare Disease Registration Service (NCARDRS). SETTING: Regions of England with active registration in the time period. PARTICIPANTS: Babies that were liveborn or stillborn and pregnancies that resulted in a termination of pregnancy or a late miscarriage (20-23 weeks' gestation) with an NTD. MAIN OUTCOME MEASURES: Total birth prevalence of anencephaly, spina bifida and all NTDs in England. Poisson regression analysis was used to evaluate time trends with regional register as a random effect. The progress of national registration across England was assessed. RESULTS: There were 4541 NTD pregnancies out of 3 637 842 births in England; 1982 anencephaly and 2127 spina bifida. NTD prevalence was 12.5 (95% CI 12.1 to 12.9) per 10 000 total births. NTD prevalence per 10 000 total births was significantly higher in 2015-2019 (13.6, 95% CI 12.9 to 14.4) compared with 2010-2014 (12.1, 95% CI 11.7 to 12.5). An increasing trend in NTDs overall was detected (incidence rate ratio (IRR) 1.01, 1.00 to 1.02), although further analysis determined this effect was confined to 2015-2019 (compared against 2000-2004, IRR 1.14, 1.04 to 1.24). The birth prevalence of anencephaly reflected this pattern. The prevalence of spina bifida remained relatively stable over time. CONCLUSIONS: Baseline NTD prevalence for England has been established. National and standardised CA registration is in place, facilitating the systematic and consistent monitoring of pre-fortification and post-fortification NTD trends and evaluating the impact of fortification on NTD prevalence.
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Anencefalia , Defeitos do Tubo Neural , Disrafismo Espinal , Gravidez , Feminino , Humanos , Ácido Fólico , Farinha , Prevalência , Anencefalia/epidemiologia , Anencefalia/prevenção & controle , Estudos de Coortes , Triticum , Alimentos Fortificados , Defeitos do Tubo Neural/epidemiologia , Defeitos do Tubo Neural/prevenção & controle , Disrafismo Espinal/epidemiologia , Disrafismo Espinal/prevenção & controleRESUMO
BACKGROUND: Equitable access to surgical care has clinical and policy implications. We assess the association between social disadvantage and wait times for elective surgical procedures in Ontario. METHODS: We conducted a cross-sectional analysis using administrative data sets of adults receiving nonurgent inguinal hernia repair, cholecystectomy, hip arthroplasty, knee arthroplasty, arthroscopy, benign uterine surgery and cataract surgery from April 2013 to December 2019. We assessed the relation between exceeding target wait times and the highest versus lowest quintile of marginalization dimensions by use of generalized estimating equations logistic regression. RESULTS: Of the 1 385 673 procedures included, 174 633 (12.6%) exceeded the target wait time. Adjusted analysis for cataract surgery found significantly increased odds of exceeding wait times for residential instability (adjusted odd ratio [OR] 1.16, 95% confidence interval [CI] 1.11-1.21) and recent immigration (adjusted OR 1.12, 95% CI 1.07-1.18). The highest deprivation quintile was associated with 18% (adjusted OR 1.18, 95% CI 1.12-1.24) and 20% (adjusted OR 1.20, 95% CI 1.12-1.28) increased odds of exceeding wait times for knee and hip arthroplasty, respectively. Residence in areas where higher proportions of residents self-identify as being part of a visible minority group was independently associated with reduced odds of exceeding target wait times for hip arthroplasty (adjusted OR 0.82, 95% CI 0.75-0.91), cholecystectomy (adjusted OR 0.68, 95% CI 0.59-0.79) and hernia repair (adjusted OR 0.65, 95% CI 0.56-0.77) with an opposite effect in benign uterine surgery (adjusted OR 1.28, 95% CI 1.17-1.40). INTERPRETATION: Social disadvantage had a small and inconsistent impact on receiving care within wait time targets. Future research should consider these differences as they relate to resource distribution and the organization of clinical service delivery.
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Walk-in clinics are typically viewed as high-volume locations for managing acute issues but also may serve as a location for primary care, including cancer screening, for patients without a family physician. In this population-based cohort study, we compared breast, cervical and colorectal cancer screening up-to-date status for people living in the Canadian province of Ontario who were formally enrolled to a family physician versus those not enrolled but who had at least one encounter with a walk-in clinic physician in the previous year. Using provincial administrative databases, we created two mutually exclusive groups: i) those who were formally enrolled to a family physician, ii) those who were not enrolled but had at least one visit with a walk-in clinic physician from April 1, 2019 to March 31, 2020. We compared up to date status for three cancer screenings as of April 1, 2020 among screen-eligible people. We found that people who were not enrolled and had seen a walk-in clinic physician in the previous year consistently were less likely to be up to date on cancer screening than Ontarians who were formally enrolled with a family physician (46.1% vs. 67.4% for breast, 45.8% vs. 67.4% for cervical, 49.5% vs. 73.1% for colorectal). They were also more likely to be foreign-born and to live in structurally marginalized neighbourhoods. New methods are needed to enable screening for people who are reliant on walk-in clinics and to address the urgent need in Ontario for more primary care providers who deliver comprehensive, longitudinal care.
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Neoplasias , Médicos , Humanos , Ontário , Detecção Precoce de Câncer/métodos , Estudos Retrospectivos , Estudos de Coortes , Programas de RastreamentoRESUMO
Storytelling has long been considered an effective means of communication, allowing the teller to process their emotions in light of particular life challenges. Effects on the listener also have been demonstrated to be beneficial, especially if the listener is faced with a similar life challenge. Less is known regarding the potential effects of storytelling on listening dyads and opportunities for joint processing following exposure to relevant stories. We sought to study these phenomena in the context of hematopoietic cell transplantation (HCT), a demanding medical procedure requiring intensive informal caregiving and thus great patient-caregiver entwinement. The purpose of this qualitative descriptive study was to explore participants' perceptions of a 4-week web-based digital storytelling (DST) intervention using both quantitative ratings of acceptability and qualitative coding of interviews conducted after intervention completion. A total of 202 participants (101 HCT patient-caregiver dyads) were recruited from the Mayo Clinic Arizona and randomized into either a DST arm or an Information Control (IC) arm. Participants in the DST arm rated the acceptability of the intervention and were asked to participate in a 30-minute phone interview to discuss their experience with the DST intervention. All interviews were recorded and transcribed verbatim and imported into NVivo 12 for coding and analysis, using a combination of deductive and inductive approaches to organize the data, create categories, and develop themes and subthemes. A total of 38 participants (19 HCT patient-caregiver dyads) completed the post-intervention interviews. Patients were 63% male and 82% White, 68% received allogeneic HCT, and their mean age was 55 years. The median time from HCT was 25 days (range, 6 to 56 days). Caregivers were mostly patients' spouses (73%) and female (69%), with a mean age of 56 years. In general, the 4-week web-based DST intervention was well accepted and liked by both patients and caregivers regarding the duration, dyadic participation, and convenience of participating in the intervention at home. Patients and caregivers who completed the DST intervention indicated that they were satisfied with the intervention (mean score, 4.5 of 5), were likely to recommend it to others (mean score, 4.4), would watch more stories (mean score, 4.1), and that the experience was worth their time (mean score, 4.6). Major themes that emerged from the qualitative analysis included (1) building communal connection through engaging with the stories; (2) positive emotional growth after HCT; (3) value of gaining the other's perspective; and (4) impact of open communication on the patient-caregiver relationship. A web-based DST intervention provides an attractive format through which to deliver a nonpharmacologic psychosocial intervention to HCT patient-caregiver dyads. Watching the emotional content in digital stories may help patients and caregivers cope with psychoemotional challenges together and provide an opportunity for emotional disclosure. Further work on determining optimal paths to disclosure is warranted.
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Cuidadores , Transplante de Células-Tronco Hematopoéticas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cuidadores/psicologia , Comunicação , Emoções , Transplante de Células-Tronco Hematopoéticas/métodos , PacientesRESUMO
High grade gliomas (HGG) have a dismal prognosis with survival rates of 15-35%. Approximately 10-12% of pediatric HGG occur in young children and their molecular biology and clinical outcomes differ from those arising at older ages. We report on four children aged <5 years newly diagnosed with non-brainstem HGG between 2011 and 2018 who were treated with surgery and BBSFOP chemotherapy. Two died of tumor progression. The other two are still alive without radiotherapy at 3.8 and 3.9 years from diagnosis: one of whom remains disease-free off treatment; and the other one, whose tumor harbored a KCTD16:NTRK2 fusion, went on to receive larotrectinib. Additionally we review the general management, outcomes and latest updates in molecular biology and targeted therapies for young children with HGG. Infant gliomas can be stratified in molecular subgroups with clinically actionable oncogenic drivers. Chemotherapy-based strategies can avoid or delay the need for radiotherapy in young children with HGG. Harnessing the potential of NTRK, ALK, ROS1 and MET inhibitors offers the opportunity to optimize the therapeutic armamentarium to improve current outcomes for these children.
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Neoplasias Encefálicas , Glioma , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Pré-Escolar , Glioma/genética , Glioma/terapia , Humanos , LactenteRESUMO
Importance: The association of low-value testing with downstream care and clinical outcomes among primary care outpatients is unknown to date. Objective: To assess the association of low-value testing with subsequent care among low-risk primary care outpatients undergoing an annual health examination (AHE). Design, Setting, and Participants: This population-based retrospective cohort study used administrative health care claims from Ontario, Canada, for primary care outpatients undergoing an AHE between April 1, 2012, and March 31, 2016, to identify individuals who could be placed into one (or more) of the following 3 cohorts: adult patients (18 years or older) at low risk for cardiovascular and pulmonary disease, adult patients at low risk for cardiovascular disease, and female patients (aged 13-20 years or older than 69 years) at low risk for cervical cancer. The dates of analysis were June 3 to September 12, 2019. Exposures: Low-value screening tests were defined per cohort as (1) a chest radiograph within 7 days, (2) an electrocardiogram (ECG) within 30 days, or (3) a Papanicolaou test within 7 days after an AHE. Main Outcomes and Measures: Subsequent specialist visits, diagnostic tests, and procedures within 90 days after a low-value test (if the patient had a chest radiograph, ECG, or Papanicolaou test) or end of the exposure observation window (if not tested). Results: Included in the chest radiograph, ECG, and Papanicolaou test cohorts of propensity score-matched pairs were 43â¯532 patients (mean [SD] age, 47.5 [14.4] years; 38.5% female), 245â¯686 patients (mean [SD] age, 49.9 [13.7] years; 51.1% female), and 29â¯194 patients (mean [SD] age, 45.5 [27.1] years; 100% female), respectively. At 90 days, chest radiographs in low-risk patients were associated with an additional 0.87 (95% CI, 0.69-1.05) and 1.96 (95% CI, 1.71-2.22) patients having an outpatient pulmonology visit or an abdominal or thoracic computed tomography scan per 100 patients, respectively, and ECGs in low-risk patients were associated with an additional 1.92 (95% CI, 1.82-2.02), 5.49 (95% CI, 5.33-5.65), and 4.46 (95% CI, 4.31-4.61) patients having an outpatient cardiologist visit, a transthoracic echocardiogram, or a cardiac stress test per 100 patients, respectively. At 180 days, Papanicolaou testing in low-risk patients was associated with an additional 1.31 (95% CI, 0.84-1.78), 52.8 (95% CI, 51.9-53.6), and 0.84 (95% CI, 0.66-1.01) patients having an outpatient gynecology visit, a follow-up Papanicolaou test, or colposcopy per 100 patients, respectively. Conclusions and Relevance: Observed associations in this population-based cohort study suggest that testing in low-risk patients as part of an AHE increases the likelihood of subsequent specialist visits, diagnostic tests, and procedures.
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Atenção à Saúde/estatística & dados numéricos , Testes Diagnósticos de Rotina/métodos , Pacientes Ambulatoriais , Vigilância da População/métodos , Atenção Primária à Saúde/estatística & dados numéricos , Pontuação de Propensão , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: Many evidence-based recommendations advocate against the use of routine chest x-rays for asymptomatic, low-risk outpatients; however, it is unclear how regularly chest x-rays are ordered in primary care. Our study aims to describe the frequency of, and variation in, routine chest x-ray use in low-risk outpatients among primary care physicians. METHODS: In this retrospective cohort study, Ontario residents aged 18 years and older with a periodic health examination (PHE) between Apr. 1, 2010, and Mar. 31, 2015, were identified via administrative claims data. Patients with a recent history (last 3 years) of any of the following were excluded: cardiac or pulmonary disease, high-risk comorbidity (e.g., diabetes), consultations/visits or procedures involving cardiac or pulmonary specialists, cancer and severe chest trauma. The primary outcome, a routine chest x-ray, was defined as at least 1 chest x-ray claim within 7 days after a PHE. RESULTS: While a routine chest x-ray followed only 2.42% of 2 847 508 PHEs, one-quarter of family physicians (499/2031) ordered chest x-rays for more than 5.0% of their PHEs (interquartile range 1.5%-5.0%) and accounted for 62.9% of all tests observed. Routine chest x-ray use declined by 2.0% per quarter (adjusted rate ratio 0.98, 95% confidence interval [CI] 0.97-0.98). Older age (45-64 yr v. 18-44 yr, adjusted odds ratio [OR] 1.82, 95% CI 1.78-1.86; ≥ 65 yr v. 18-44 yr, adjusted OR 2.48, 95% CI 2.39-2.58) and male sex of the patient (OR 2.19, 95% CI 2.14-2.24) and male sex of the provider (OR 1.55, 95% CI 1.51-1.59) were significantly associated with increased odds of a routine chest x-ray being ordered. INTERPRETATION: It is relatively uncommon for a chest x-ray to be ordered as part of a PHE in Ontario; however, the substantial variation observed among physicians suggests potential for interventions targeted at the most frequent users.
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Access to health care based on need rather than ability to pay was the founding principle of the Canadian health-care system. Medicare was born in one province in 1947. It spread across the country through federal cost sharing, and eventually was harmonised through standards in a federal law, the Canada Health Act of 1984. The health-care system is less a true national system than a decentralised collection of provincial and territorial insurance plans covering a narrow basket of services, which are free at the point of care. Administration and service delivery are highly decentralised, although coverage is portable across the country. In the setting of geographical and population diversity, long waits for elective care demand the capacity and commitment to scale up effective and sustainable models of care delivery across the country. Profound health inequities experienced by Indigenous populations and some vulnerable groups also require coordinated action on the social determinants of health if these inequities are to be effectively addressed. Achievement of the high aspirations of Medicare's founders requires a renewal of the tripartite social contract between governments, health-care providers, and the public. Expansion of the publicly funded basket of services and coordinated effort to reduce variation in outcomes will hinge on more engaged roles for the federal government and the physician community than have existed in previous decades. Public engagement in system stewardship will also be crucial to achieve a high-quality system grounded in both evidence and the Canadian values of equity and solidarity.
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Acessibilidade aos Serviços de Saúde/organização & administração , Programas Nacionais de Saúde/organização & administração , Cobertura Universal do Seguro de Saúde/organização & administração , Canadá , HumanosRESUMO
Importance: Efforts to reduce low-value tests and treatments in primary care are often ineffective. These efforts typically target physicians broadly, most of whom order low-value care infrequently. Objectives: To measure physician-level use rates of 4 low-value screening tests in primary care to investigate the presence and characteristics of primary care physicians who frequently order low-value care. Design, Setting, and Participants: A retrospective cohort study was conducted using administrative health care claims collected between April 1, 2012, and March 31, 2016, in Ontario, Canada. This study measured use of 4 low-value screening tests-repeated dual-energy x-ray absorptiometry (DXA) scans, electrocardiograms (ECGs), Papanicolaou (Pap) tests, and chest radiographs (CXRs)-among low-risk outpatients rostered to a common cohort of primary care physicians. Exposures: Physician sex, years since medical school graduation, and primary care model. Main Outcomes and Measures: This study measured the number of tests to which a given physician ranked in the top quintile by ordering rate. The resulting cross-test score (range, 0-4) reflects a physician's propensity to order low-value care across screening tests. Physicians were then dichotomized into infrequent or isolated frequent users (score, 0 or 1, respectively) or generalized frequent users for 2 or more tests (score, ≥2). Results: The final sample consisted of 2394 primary care physicians (mean [SD] age, 51.3 [10.0] years; 50.2% female), who were predominantly Canadian medical school graduates (1701 [71.1%]), far removed from medical school graduation (median, 25.3 years; interquartile range, 17.3-32.3 years), and reimbursed via fee-for-service in a family health group (1130 [47.2%]). They ordered 302â¯509 low-value screening tests (74â¯167 DXA scans, 179â¯855 ECGs, 19â¯906 Pap tests, and 28â¯581 CXRs) after 3â¯428â¯557 ordering opportunities. Within the cohort, generalized frequent users represented 18.4% (441 of 2394) of physicians but ordered 39.2% (118 665 of 302 509) of all low-value screening tests. Physicians who were male (odds ratio, 1.29; 95% CI, 1.01-1.64), further removed from medical school graduation (odds ratio, 1.03; 95% CI, 1.02-1.04), or in an enhanced fee-for-service payment model (family health group) vs a capitated payment model (family health team) (odds ratio, 2.04; 95% CI, 1.42-2.94) had increased odds of being generalized frequent users. Conclusions and Relevance: This study identified a group of primary care physicians who frequently ordered low-value screening tests. Tailoring future interventions to these generalized frequent users might be an effective approach to reducing low-value care.
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Programas de Rastreamento/estatística & dados numéricos , Médicos de Atenção Primária/estatística & dados numéricos , Padrões de Prática Médica/estatística & dados numéricos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ontário/epidemiologia , Estudos RetrospectivosRESUMO
Cervical cancer incidence and mortality rates are significantly higher in low- and middle-income countries compared with the United States and other developed countries. This disparity is caused by decreased access to screening, often coupled with low numbers of trained providers offering cancer prevention and treatment services. However, similar disparities are also found in underserved areas of the United States, such as the Texas-Mexico border, where cervical cancer mortality rates are 30% higher than in the rest of Texas. To address these issues, we have adopted the Project ECHO (Extension for Community Healthcare Outcomes) program, a low-cost telementoring model previously proven to be successful in increasing local capacity, improving patient management skills, and ultimately improving patient outcomes in rural and underserved areas. We use the Project ECHO model to educate local providers in the management of cervical dysplasia in a low-resource region of Texas and have adapted it to inform strategies for the management of advanced cervical and breast cancer in Latin America and sub-Saharan Africa. This innovative approach, using ECHO, is part of a larger strategy to enhance clinical skills and develop collaborative projects between academic centers and partners in low-resource regions.
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Importance: Clinical guidelines advise against routine electrocardiograms (ECG) in low-risk, asymptomatic patients, but the frequency and impact of such ECGs are unknown. Objective: To assess the frequency of ECGs following an annual health examination (AHE) with a primary care physician among patients with no known cardiac conditions or risk factors, to explore factors predictive of receiving an ECG in this clinical scenario, and to compare downstream cardiac testing and clinical outcomes in low-risk patients who did and did not receive an ECG after their AHE. Design, Setting, and Participants: A population-based retrospective cohort study using administrative health care databases from Ontario, Canada, between 2010/2011 and 2014/2015 to identify low-risk primary care patients and to assess the subsequent outcomes of interest in this time frame. All patients 18 years or older who had no prior cardiac medical history or risk factors who received an AHE. Exposures: Receipt of an ECG within 30 days of an AHE. Main Outcomes and Measures: Primary outcome was receipt of downstream cardiac testing or consultation with a cardiologist. Secondary outcomes were death, hospitalization, and revascularization at 12 months. Results: A total of 3â¯629â¯859 adult patients had at least 1 AHE between fiscal years 2010/2011 and 2014/2015. Of these patients, 21.5% had an ECG within 30 days after an AHE. The proportion of patients receiving an ECG after an AHE varied from 1.8% to 76.1% among 679 primary care practices (coefficient of quartile dispersion [CQD], 0.50) and from 1.1% to 94.9% among 8036 primary care physicians (CQD, 0.54). Patients who had an ECG were significantly more likely to receive additional cardiac tests, visits, or procedures than those who did not (odds ratio [OR], 5.14; 95% CI, 5.07-5.21; P < .001). The rates of death (0.19% vs 0.16%), cardiac-related hospitalizations (0.46% vs 0.12%), and coronary revascularizations (0.20% vs 0.04%) were low in both the ECG and non-ECG cohorts. Conclusions and Relevance: Despite recommendations to the contrary, ECG testing after an AHE is relatively common, with significant variation among primary care physicians. Routine ECG testing seems to increase risk for a subsequent cardiology testing and consultation cascade, even though the overall cardiac event rate in both groups was very low.
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Eletrocardiografia/métodos , Cardiopatias , Adulto , Idoso , Canadá/epidemiologia , Feminino , Cardiopatias/diagnóstico , Cardiopatias/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Padrões de Prática Médica , Atenção Primária à Saúde/métodos , Atenção Primária à Saúde/organização & administração , Encaminhamento e Consulta/estatística & dados numéricos , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Procedimentos Desnecessários/métodos , Procedimentos Desnecessários/estatística & dados numéricosAssuntos
Neoplasias da Mama/epidemiologia , Mamoplastia/estatística & dados numéricos , Mastectomia/estatística & dados numéricos , Adulto , Neoplasias da Mama/radioterapia , Neoplasias da Mama/cirurgia , Feminino , Disparidades em Assistência à Saúde , Humanos , Moçambique/epidemiologia , Serviços de Saúde da MulherAssuntos
Técnicas de Laboratório Clínico/economia , Procedimentos Desnecessários , Atitude do Pessoal de Saúde , Canadá , Diagnóstico Precoce , Necessidades e Demandas de Serviços de Saúde , Humanos , Programas de Rastreamento , Participação do Paciente , Guias de Prática Clínica como Assunto , Reembolso de IncentivoRESUMO
Vascular smooth muscle (VSM) proliferation and migration are key components in vessel remodeling. Cyclic nucleotide signaling is protective and has long-served as a therapeutic target against undesired VSM growth. The present work analyzed the effects of the soluble guanylate cyclase (sGC) stimulator 3-(4-amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine [BAY 41-2272 (BAY)] on VSM growth, and we hypothesize that BAY has the capacity to reduce proliferation and migration via cyclic nucleotide-driven kinase signaling. Perivascular BAY postballoon injury reduced neointimal growth by â¼ 40% compared with vehicle controls after 2 weeks. In VSM cells, BAY (10 µM) reduced proliferation by â¼ 40% after 72 h and migration by â¼ 40% after 6 h and â¼ 60% after 18 h without deleterious effects on cell viability. cGMP content peaked (248 ×) 20 min after BAY treatment and remained elevated (140 ×) through 60 min; however, BAY did not affect cAMP levels compared with controls. Conventional and In-Cell Western analyses showed increases in vasodilator-stimulated phosphoprotein (VASP) phosphorylation (pVASP) at serines 239 (3 ×) and 157 (2 ×), respective markers of cGMP- and cAMP-directed protein kinases (PKG and PKA, respectively). The PKG inhibitor YGRKKRRQRRRPPLRKKKKKH peptide (DT-2) completely reversed BAY-mediated increases in pVASPSer(239) and BAY-mediated inhibition of migration. In comparison, the PKA inhibitor peptide PKI further potentiated BAY-stimulated pVASPSer(157) and pVASPSer(239) and partially reversed the antiproliferative effects of BAY. This is the first report demonstrating the effectiveness of BAY in reducing neointimal growth with direct evidence for PKG-specific antimigratory and PKA-specific antiproliferative mechanisms. Conclusively, the sGC stimulator BAY reduces VSM growth through cGMP-dependent PKG and PKA processes, providing support for continued evaluation of its clinical utility.
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Proliferação de Células/efeitos dos fármacos , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Inibidores do Crescimento/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Pirazóis/farmacologia , Piridinas/farmacologia , Receptores Citoplasmáticos e Nucleares/agonistas , Administração Tópica , Animais , Lesões das Artérias Carótidas/tratamento farmacológico , Lesões das Artérias Carótidas/patologia , Ciclo Celular/efeitos dos fármacos , Ensaios de Migração Celular , Sobrevivência Celular/efeitos dos fármacos , AMP Cíclico/análise , GMP Cíclico/análise , Inibidores do Crescimento/administração & dosagem , Inibidores do Crescimento/uso terapêutico , Guanilato Ciclase , Masculino , Terapia de Alvo Molecular , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/fisiologia , Fosforilação/efeitos dos fármacos , Pirazóis/administração & dosagem , Pirazóis/uso terapêutico , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Guanilil Ciclase SolúvelRESUMO
BACKGROUND: Although colonoscopy is increasingly performed in nonhospital facilities, studies to date examining differences between colonoscopy services in hospital and nonhospital settings have been limited, in large part, to administrative databases. OBJECTIVES: To describe the experiences of patients receiving colonoscopy in hospital and nonhospital settings, and to compare these settings with respect to wait times and recommended follow-up interval to the next colonoscopy. METHODS: A postal survey of 2000 patients, 50 to 70 years of age, from an urban academic family practice was conducted. Most recent colonoscopy was classified as either occurring in a hospital or nonhospital setting. Multivariable logistic regression analysis was used to examine the association among wait times, follow-up intervals and patient factors with respect to colonoscopy setting. RESULTS: Patients who underwent their most recent colonoscopy outside of a hospital were more likely to be men (P=0.01) and to have undergone more than one previous colonoscopy (P=0.02). For patients with a normal screening colonoscopy and no family history of colorectal cancer or polyps, nonhospital clinics less often recommended a 10-year follow-up interval (OR 0.13 [95% CI 0.04 to 0.47]). Reported wait times at nonhospital clinics were shorter for patients receiving screening colonoscopy (OR 2.11 [95% CI 1.28 to 3.47]), but not for symptomatic patients (OR 1.74 [95% CI 0.88 to 3.43]). For individuals attending nonhospital clinics, 10% were referred from a hospital by the same specialist performing the procedure; 31.7% reported paying a fee. CONCLUSION: Nonhospital clinics were far less likely to adhere to guidelines regarding follow-up intervals for low-risk patients. Given the implications for both health care costs and patient safety, further study is needed to determine the cause of this disparity.
Assuntos
Colonoscopia/estatística & dados numéricos , Fidelidade a Diretrizes/estatística & dados numéricos , Idoso , Instituições de Assistência Ambulatorial/estatística & dados numéricos , Neoplasias do Colo/prevenção & controle , Colonoscopia/economia , Continuidade da Assistência ao Paciente , Feminino , Hospitais/estatística & dados numéricos , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Ontário , Neoplasias Retais/prevenção & controleRESUMO
Conformational preferences of the nicotine analogue 2-phenylpyrrolidine (PPD) have been studied in both gaseous and solution phases. Theoretical calculations at the MP2 and B3LYP levels point to 5-6 stable conformers which differ in three degrees of conformational freedom; torsion between the two rings, inversion at the pyrrolidine (PY) amine, and PY ring puckering, characterized using the Cremer-Pople definition for pseudorotation. Only one conformer has a trans arrangement between the amino hydrogen and the phenyl substituent. It is 6-8 kJ mol(-1) more stable than the cis conformers, has a perpendicular ring arrangement, and puckers at the nitrogen atom--similar to structures reported for nicotine. Resonant two-photon ionization (R2PI) data, including hole burn spectra, indicate only one conformer is present in the free jet expansion, and band contour analysis suggests assignment to the trans conformer. Confirmation was provided by microwave spectroscopy. Fifty-seven lines measured in the 48-72 GHz region were assigned to 206 b-type transitions and fitted to yield rotational constants within 2 MHz of MP2 values predicted for the trans conformer. The solution-phase conformers of PPD were studied using 1D and 2D (1)H NMR spectroscopy and solvent-based theoretical calculations. In marked contrast to the gas phase, NMR data reveals only cis conformers present in solution. Calculations confirm increased stability for these conformers when placed in simulated chloroform or water environments. Solvent molecules are believed to disrupt a crucial N...H(ortho) stabilizing interaction present within the trans conformer.