RESUMEN
INTRODUCTION: Most patients with advanced gallbladder cancer are treated with multiagent chemotherapy. Immune checkpoint inhibitors offer the possibility of a durable response with less toxicity. This prospective, multicenter, open-label study was designed to evaluate the anticancer activity of nivolumab plus ipilimumab in patients with advanced gallbladder cancer. METHODS: Nineteen patients with advanced gallbladder cancer refractory to ≥1 previous therapy received nivolumab 240 mg intravenously every 2 weeks and ipilimumab 1 mg/kg intravenously every 6 weeks until disease progression or unacceptable toxicity. The primary end point was confirmed radiographic overall response rate (ORR) (complete response [CR] + partial response [PR] confirmed on subsequent scan); secondary end points included unconfirmed overall response, clinical benefit rate (confirmed and unconfirmed responses + stable disease >6 months), progression-free survival, overall survival, and toxicity. RESULTS: The confirmed ORR was 16% (CR, n = 1 [5%]; PR, n = 2 [11%]); all were microsatellite stable, and the confirmed CR had undetectable programmed death-ligand 1 by immunohistochemistry. The unconfirmed ORR and clinical benefit rates were both 32%. The median duration of response was 14.8 months (range, 4-35.1+ months). The 6-month progression-free survival was 26% (95% CI, 12-55). The median overall survival was 7.0 months (95% CI, 3.9-19.1). The most common toxicities were fatigue (32%), anemia (26%), and anorexia (26%). Aspartate aminotransferase elevation was the most common grade 3/4 toxicity (11%). There was 1 possibly related death (sepsis with attendant hepatic failure). CONCLUSIONS: Ipilimumab plus nivolumab was well tolerated and showed modest efficacy with durable responses in previously treated patients with advanced gallbladder cancer. CLINICAL TRIAL REGISTRATION: NCT02834013 (ClincialTrials.gov). PLAIN LANGUAGE SUMMARY: This prospective study assessed the efficacy and safety of nivolumab plus ipilimumab in 19 patients with advanced gallbladder cancer refractory to previous therapy. The combination demonstrated modest efficacy with a 16% confirmed overall response rate, durable responses, and manageable toxicities, suggesting potential benefits for this challenging patient population.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Antígeno CTLA-4 , Neoplasias de la Vesícula Biliar , Ipilimumab , Nivolumab , Receptor de Muerte Celular Programada 1 , Humanos , Neoplasias de la Vesícula Biliar/tratamiento farmacológico , Neoplasias de la Vesícula Biliar/patología , Femenino , Masculino , Persona de Mediana Edad , Anciano , Ipilimumab/administración & dosificación , Ipilimumab/uso terapéutico , Ipilimumab/efectos adversos , Nivolumab/administración & dosificación , Nivolumab/uso terapéutico , Nivolumab/efectos adversos , Antígeno CTLA-4/antagonistas & inhibidores , Estudios Prospectivos , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Adulto , Supervivencia sin Progresión , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Patients undergoing resection of renal cell carcinoma are at risk of disease relapse. We evaluated the effectiveness of the mammalian target of rapamycin inhibitor everolimus administered after surgery. METHODS: In this randomised, double-blind, phase 3 trial, we enrolled adults with histologically confirmed renal cell carcinoma who had undergone a full surgical resection and were at intermediate-high or very high risk of recurrence at 398 academic and community institution centres in the USA. After nephrectomy, patients were randomly assigned (1:1) via a central web-based application using a dynamic balancing algorithm to receive 10 mg oral everolimus daily or placebo for 54 weeks. The primary endpoint was recurrence-free survival. Efficacy analyses included all eligible, randomly assigned patients; safety analysis included all patients who received treatment. This trial is registered with ClinicalTrials.gov, NCT01120249 and is closed to new participants. FINDINGS: Between April 1, 2011, and Sept 15, 2016, a total of 1545 patients were randomly assigned to receive everolimus (n=775) or placebo (n=770), of whom 755 assigned to everolimus and 744 assigned to placebo were eligible for inclusion in the efficacy analysis. With a median follow-up of 76 months (IQR 61-92), recurrence-free survival was longer with everolimus than with placebo (5-year recurrence-free survival 67% [95% CI 63-70] vs 63% [60-67]; stratified log-rank p=0·050; stratified hazard ratio [HR] 0·85, 95% CI 0·72-1·00; p=0·051) but did not meet the prespecified p value for statistical significance of 0·044. Recurrence-free survival was longer with everolimus than with placebo in the very-high-risk group (HR 0·79, 95% CI 0·65-0·97; p=0·022) but not in the intermediate-high-risk group (0·99, 0·73-1·35; p=0·96). Grade 3 or higher adverse events occurred in 343 (46%) of 740 patients who received everolimus and 79 (11%) of 723 who received placebo. INTERPRETATION: Postoperative everolimus did not improve recurrence-free survival compared with placebo among patients with renal cell carcinoma at high risk of recurrence after nephrectomy. These results do not support the adjuvant use of everolimus for renal cell carcinoma after surgery. FUNDING: US National Institutes of Health, National Cancer Institute, National Clinical Trials Network, Novartis Pharmaceuticals Corporation, and The Hope Foundation.
Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Estados Unidos , Adulto , Humanos , Everolimus/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/cirugía , Recurrencia Local de Neoplasia/tratamiento farmacológico , Sirolimus/uso terapéutico , Adyuvantes Inmunológicos/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/cirugíaRESUMEN
OBJECTIVE: Non-Hispanic (NH) Black children are less likely to receive a standard treatment course for infantile epileptic spasms syndrome (IESS) than White/NH children at pediatric tertiary care epilepsy centers in the United States. However, if inequities exist in time to diagnosis is unknown. Diagnostic delays as little as 1 week can be associated with worse developmental outcomes. METHODS: Diagnostic delays were evaluated in a retrospective cohort of 100 children with new onset IESS between January 2019 and May 2022. RESULTS: Children with Black, Indigenous, and People of Color (BIPOC) caregivers were more likely to experience clinically significant delays in referral from first provider to neurologist, when compared to White/NH children, even after controlling for other demographic and clinical variables (odds ratio = 4.98, confidence interval = 1.24-19.94, p = .023). SIGNIFICANCE: Disproportionate diagnostic delays place BIPOC children at risk of adverse developmental and epilepsy outcomes. Further interventional prospective and qualitative studies are needed to address inequities in care.
Asunto(s)
Epilepsia , Espasmos Infantiles , Humanos , Niño , Estados Unidos , Estudios Retrospectivos , Estudios Prospectivos , Etnicidad , Epilepsia/diagnóstico , Síndrome , Espasmo , Espasmos Infantiles/terapia , Espasmos Infantiles/tratamiento farmacológicoRESUMEN
AIMS: Community treatment orders have been introduced in many jurisdictions with increasing use over time. We conducted a rapid umbrella review to synthesise the quantitative and qualitative evidence from systematic reviews and/or meta-analyses of their potential harms and benefits. METHODS: A systematic search of Medline, PubMed, Embase and PsycINFO for relevant systematic reviews and/or meta-analyses. Where available, participants on community treatment orders were compared with controls receiving voluntary psychiatric treatment. This review is registered with PROSPERO (CRD42023398767) and the Open Science Framework (https://osf.io/zeq35). RESULTS: In all, 17 publications from 14 studies met the inclusion criteria. Quantitative synthesis of data from different systematic reviews was not possible. There were mixed findings on the effects of community treatment orders on health service use, and clinical, psychosocial or forensic outcomes. Whereas uncontrolled evidence suggested benefits, results were more equivocal from controlled studies and randomised controlled trials showed no effect. Any changes in health service use took several years to become apparent. There was evidence that better targeting of community treatment order use led to improved outcomes. Although there were other benefits, such as in mortality, findings were mostly rated as suggestive using predetermined and standardised criteria. Qualitative findings suggested that family members and clinicians were generally positive about the effect of community treatment orders but those subjected to them were more ambivalent. Any possible harms were under-researched, particularly in quantitative designs. CONCLUSIONS: The evidence for the benefits of community treatment orders remains inconclusive. At the very least, use should be better targeted to people most likely to benefit. More quantitative research on harms is indicated.
Asunto(s)
Servicios Comunitarios de Salud Mental , Trastornos Mentales , Humanos , Trastornos Mentales/terapia , Servicios Comunitarios de Salud Mental/normas , Revisiones Sistemáticas como AsuntoRESUMEN
RNA folding is driven by the formation of double-helical segments interspaced by loops of unpaired nucleotides. Among the latter, bulges formed by one or several unpaired nucleotides are one of the most common structural motifs that play an important role in stabilizing RNA-RNA, RNA-protein, and RNA-small molecule interactions. Single-nucleotide bulges can fold in alternative structures where the unpaired nucleobase is either looped-out (flexible) in a solvent or stacked-in (intercalated) between the base pairs. In the present study, we discovered that triplex-forming peptide nucleic acids (PNAs) had unusually high affinity for single-purine-nucleotide bulges in double-helical RNA. Depending on the PNA's sequence, the triplex formation shifted the equilibrium between looped-out and stacked-in conformations. The ability to control the dynamic equilibria of RNA's structure will be an important tool for studying structure-function relationships in RNA biology and may have potential in novel therapeutic approaches targeting disease-related RNAs.
Asunto(s)
Ácidos Nucleicos de Péptidos , ARN , ARN/química , Ácidos Nucleicos de Péptidos/química , Conformación de Ácido Nucleico , Emparejamiento Base , Nucleótidos/químicaRESUMEN
INTRODUCTION: Prosthesis choice during aortic valve replacement (AVR) weighs lifelong anticoagulation with mechanical valves (M-AVR) against structural valve degeneration in bioprosthetic valves (B-AVR). METHODS: The Nationwide Readmissions Database was queried to identify patients who underwent isolated surgical AVR between January 1, 2016 and December 31, 2018, stratifying by prothesis type. Propensity score matching was used to compare risk-adjusted outcomes. Readmission at 1 y was estimated with Kaplan-Meier (KM) analysis. RESULTS: Patients (n = 109,744) who underwent AVR (90,574 B-AVR and 19,170 M-AVR) were included. B-AVR patients were older (median 68 versus 57 y; P < 0.001) and had more comorbidities (mean Elixhauser score: 11.8 versus 10.7; P < 0.001) compared to M-AVR patients. After matching (n = 36,951), there was no difference in age (58 versus 57 y; P = 0.6) and Elixhauser score (11.0 versus 10.8; P = 0.3). B-AVR patients had similar in-hospital mortality (2.3% versus 2.3%; P = 0.9) and cost (mean: $50,958 versus $51,200; P = 0.4) compared with M-AVR patients. However, B-AVR patients had shorter length of stay (8.3 versus 8.7 d; P < 0.001) and fewer readmissions at 30 d (10.3% versus 12.6%; P < 0.001) and 90 d (14.8% versus 17.8%; P < 0.001), and 1 y (P < 0.001, KM analysis). Patients undergoing B-AVR were less likely to be readmitted for bleeding or coagulopathy (5.7% versus 9.9%; P < 0.001) and effusions (9.1% versus 11.9%; P < 0.001). CONCLUSIONS: B-AVR patients had similar early outcomes compared to M-AVR patients, but lower rates of readmission. Bleeding, coagulopathy, and effusions are drivers of excess readmissions in M-AVR patients. Readmission reduction strategies targeting bleeding and improved anticoagulation management are warranted in the first year following AVR.
Asunto(s)
Bioprótesis , Implantación de Prótesis de Válvulas Cardíacas , Humanos , Válvula Aórtica/cirugía , Readmisión del Paciente , Implantación de Prótesis de Válvulas Cardíacas/efectos adversos , Resultado del Tratamiento , Anticoagulantes/uso terapéutico , Estudios Retrospectivos , Diseño de PrótesisRESUMEN
The photophysics of biochromophore ions often depends on the isomeric or protomeric distribution, yet this distribution, and the individual isomer contributions to an action spectrum, can be difficult to quantify. Here, we use two separate photodissociation action spectroscopy instruments to record electronic spectra for protonated forms of the green (pHBDI+) and cyan (Cyan+) fluorescent protein chromophores. One instrument allows for cryogenic (T = 40 ± 10 K) cooling of the ions, while the other offers the ability to perform protomer-selective photodissociation spectroscopy. We show that both chromophores are generated as two protomers when using electrospray ionisation, and that the protomers have partially overlapping absorption profiles associated with the S1 â S0 transition. The action spectra for both species span the 340-460 nm range, although the spectral onset for the pHBDI+ protomer with the proton residing on the carbonyl oxygen is red-shifted by ≈40 nm relative to the lower-energy imine protomer. Similarly, the imine and carbonyl protomers are the lowest energy forms of Cyan+, with the main band for the carbonyl protomer red-shifted by ≈60 nm relative to the lower-energy imine protomer. The present strategy for investigating protomers can be applied to a wide range of other biochromophore ions.
Asunto(s)
Subunidades de Proteína , Subunidades de Proteína/química , Análisis Espectral , Proteínas Fluorescentes Verdes/química , Iones/químicaRESUMEN
BACKGROUND: Nationally, Indigenous Australians are more likely to have diabetes and diabetic retinopathy (DR) than non-Indigenous Australians. However, the prevalence of DR and impaired vision in regional primary care settings is unclear. AIM: To describe the prevalence and severity of DR and presenting vision level among Indigenous Australian adults with diabetes attending an indigenous primary care clinic in regional Australia. METHODS: Participants underwent nurse-led retinal imaging and DR screening with offsite retinal grading in the integrated Diabetes Education and Eye Screening (iDEES) project implemented at a regional indigenous primary healthcare setting between January 2018 and March 2020. RESULTS: Of 172 eligible adults, 135 (79%) were recruited and screened for DR and vision level. The median age was 56 (46-67) years, 130 (96%) had type 2 diabetes of median (interquartile range) duration 6 (2-12) years and 48 (36%) were male. Images from 132 (97.8%) participants were gradable. DR was present in 38 (29%) participants: mild non-proliferative in 33 (25%); moderate-severe in three (2.5%); and sight-threatening two (1.5%). Subnormal presenting vision was present in 33%. CONCLUSIONS: A nurse-led model of care integrating diabetes eye screening and education at a single visit was successful at recruiting Indigenous Australian adults with diabetes, screening their vision and acquiring a high rate of gradable images. Even for a short duration of known diabetes, DR was present in three out of 10 patients screened.
Asunto(s)
Aborigenas Australianos e Isleños del Estrecho de Torres , Retinopatía Diabética , Servicios de Salud del Indígena , Tamizaje Masivo , Rol de la Enfermera , Baja Visión , Femenino , Humanos , Masculino , Persona de Mediana Edad , Australia/epidemiología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiología , Retinopatía Diabética/diagnóstico , Retinopatía Diabética/epidemiología , Retinopatía Diabética/etiología , Tamizaje Masivo/métodos , Tamizaje Masivo/enfermería , Tamizaje Masivo/estadística & datos numéricos , Prevalencia , Atención Primaria de Salud/métodos , Atención Primaria de Salud/estadística & datos numéricos , Trastornos de la Visión/diagnóstico , Trastornos de la Visión/epidemiología , Trastornos de la Visión/etiología , Baja Visión/diagnóstico , Baja Visión/epidemiología , Baja Visión/etiología , Anciano , Educación del Paciente como Asunto/métodos , Educación del Paciente como Asunto/estadística & datos numéricos , Servicios de Salud del Indígena/provisión & distribución , Aborigenas Australianos e Isleños del Estrecho de Torres/estadística & datos numéricosRESUMEN
Emergency Psychiatry is evolving. In an environment that lacks a clear evidence base, and where a constellation of factors is driving up Emergency Department presentation rates and lengths of stay, several stakeholders are working towards and clamouring for change. With the goal of collaborating with such parties, we believe Emergency Psychiatrists should position themselves to establish and advocate for best-practice change in culture, research, clinical care and training, and funding in the provision of mental health crisis care. To this end, we have formed the NSW Emergency Psychiatry Network, a group of Emergency Psychiatrists with a broad experience in a range of settings, from tertiary metropolitan emergency facilities with access to subspecialty psychiatric services, to rural and remote emergency settings with sporadic in-reach from local mental health services and telehealth. We unanimously recognise the need to upskill both Emergency Department and Mental Health clinicians in crisis care, and the need for committed, evidence-based Mental Health resourcing within Emergency Departments.
Asunto(s)
Trastornos Mentales , Servicios de Salud Mental , Psiquiatría , Telemedicina , Humanos , Trastornos Mentales/psicología , Servicio de Urgencia en HospitalRESUMEN
Contemporary forest management often requires meeting diverse ecological objectives including maintaining ecosystem function and promoting biodiversity through timber harvesting. Wildlife are essential in this process by providing ecological services that can facilitate forest resiliency in response to timber harvesting. However, the mechanisms driving species' responses remain ambiguous. The goal of this study was to assess mechanisms influencing eastern red-backed salamander (RBS; Plethodon cinereus) response to overstory cover removal. We evaluated two mitigation strategies for the RBS in response to overstory removal. We used a before-after-control-impact design to study how (1) retaining residual trees or (2) eliminating soil compaction affected RBS surface counts and body condition index (BCI) up to two-years post-treatment. Additionally, we assessed how surface counts of RBS were influenced by overstory tree cover. Surface counts of RBS were not strongly influenced by overstory removal when tree residuals were retained. Body condition index increased in treatments where harvest residuals were retained. In treatments where soil compaction was eliminated, surface counts and BCI were inversely related. Finally, surface counts from both mitigation strategies were not strongly influenced by overstory cover. Overall, both mitigation techniques appeared to ameliorate impacts of overstory removal on RBS. These results highlight the importance of understanding mechanisms driving species' responses to forest management. To reduce the perceived negative effects of overstory removal on RBS, incorporating these mitigation measures may contribute to the viability and stability of RBS populations. Incorporating species' life history traits into management strategies could increase continuity of ecological function and integrity through harvesting.
Asunto(s)
Ecosistema , Bosques , Animales , Árboles , Suelo , Urodelos , Agricultura Forestal/métodosRESUMEN
This column examines conscientious objection and institutional objection in Australian voluntary assistance in dying. It reviews the current legislative regimes and then examines these practices from an ethical perspective, and raises particular concerns and suggestions with how conscientious objection and institutional objection should be operationalised.
Asunto(s)
Conciencia , Negativa al Tratamiento , Australia , Instituciones de SaludRESUMEN
AIM: To assess the prevalence of modifiable health-risk behaviours among Indigenous Australian adults with diabetes attending a regional Victorian Indigenous primary-care clinic. DESIGN: A cross-sectional observational single-site study. METHODS: As part of a multi-study project we administered the Smoking, Nutrition, Alcohol consumption, Physical activity and Emotional wellbeing (SNAPE) survey tool during the study baseline visit to methodically capture health-related behavioural data in the nurse-led integrated Diabetes Education and Eye Screening (iDEES) project in a regional Indigenous primary healthcare setting between January 2018 and March 2020. This descriptive SNAPE study helps address the lack of health behaviour data for Indigenous people with diabetes. RESULTS: Of 172 eligible adults, 135 (79%) were recruited to the iDEES study, 50 (37%) male. All participated in at least one survey. Median (range) age was 56 (46-67) years; 130 (96%) had Type 2 diabetes of median [IQR] duration 6 (2-12) years. All 135 provided smoking data; 88 (65%) completed all surveys. Forty-nine (36%) and 29 (22%) were current or former smokers, respectively; 5 (6%) met vegetable intake guidelines, 22 (25%) met fruit intake guidelines; 38 [43%] drank alcohol in the past year. On average, participants walked for ≥10 min at a time 4 days/week and sat for an average of 8 h on weekdays; 35 (40%) had minimal-mild, and 30 (34%) had moderate-severe depressive symptoms. CONCLUSION: Suboptimal modifiable health-risk behaviours and depressive symptoms are common in Indigenous Australian adults with diabetes. IMPACT: Orderly assessment and reporting of health-risk behaviours using a single multi-component survey instrument (SNAPE tool) during a nurse-led diabetes education clinical visit is feasible and efficient. Such data may facilitate personalised interventions and improve diabetes management at both individual and health service levels.
Asunto(s)
Diabetes Mellitus Tipo 2 , Adulto , Anciano , Australia/epidemiología , Estudios Transversales , Diabetes Mellitus Tipo 2/epidemiología , Femenino , Conductas Relacionadas con la Salud , Humanos , Masculino , Persona de Mediana Edad , Asunción de RiesgosRESUMEN
AIM: The aim was to describe vascular risk factors in Australian adults with diabetes attending an Indigenous primary care nurse-led diabetes clinic. DESIGN: This was a cross-sectional descriptive single-site study. METHODS: Vascular risk factor data were extracted from the electronic health records of participants in the nurse-led integrated Diabetes Education and Eye disease Screening (iDEES) study at a regional Victorian Indigenous primary health-care clinic between January 2018 and March 2020. RESULTS: Of 172 eligible adults, 135 (79%) provided data. Median (IQR) age was 56 (46-67) years; 89% were Indigenous; 95% had Type 2 diabetes of median (IQR) duration of 6 (2-12) years and 48 (36%) were male. Median HbA1c, blood pressure, cholesterol (total; LDL and HDL), triglycerides, eGFR, CRP and BMI were 8.0% (64 mmol/mol), 127/78 mm Hg, 4.2; 1.9; 1.1 mmol/L, 2.3 mmol/L, 89 ml/min/1.73 m2 , 7.0 mg/L and 32.4 kg/m2 . Of nine clinical risk factors, the median (IQR) number of risk factors at target was 4 (3-5) for women and 3 (2-5) for men, pχ2 = 0.563. Clinical targets for BMI, HbA1c, blood pressure, triglycerides, total cholesterol, LDL cholesterol, urine albumin: creatinine ratio, HDL cholesterol and smoking were met by 14%, 34%, 38%, 39%, 44%, 52%, 54%, 62% and 64%, respectively. CONCLUSION: A nurse-led model of integrated clinical risk factor assessment and diabetes education identified suboptimal levels of clinical risk factor control for avoiding diabetes chronic complications amongst Australian adults with diabetes in an Indigenous primary care setting. IMPACT: A nurse-led model of diabetes care integrating clinical risk factor assessment into a diabetes education service is achievable. Understanding by stakeholders, including people with diabetes, their clinicians and health services, of the importance of regular monitoring of risk factors impacting diabetes complications is important. The novel nurse-managed iDEES primary-care model of care can assist. TRIAL REGISTRATION: This study was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12618001204235).
Asunto(s)
Complicaciones de la Diabetes , Diabetes Mellitus Tipo 2 , Oftalmopatías , Adulto , Anciano , Albúminas , Australia , Colesterol , HDL-Colesterol , LDL-Colesterol , Creatinina , Estudios Transversales , Complicaciones de la Diabetes/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Oftalmopatías/complicaciones , Femenino , Hemoglobina Glucada/análisis , Humanos , Masculino , Persona de Mediana Edad , Rol de la Enfermera , Atención Primaria de Salud , Medición de Riesgo , TriglicéridosRESUMEN
AIMS: To determine eye screening coverage and adherence to national eye screening recommendations of a nurse-led retinal image-based model of diabetes education and eye screening in Indigenous primary care clinics. DESIGN: A pre-post study. METHODS: During January 2018-March 2020 Indigenous Australians with diabetes at three regional Australian clinics were offered eye screening by a nurse-diabetes educator/retinal imager. At the main site the nurse recruited/scheduled participants, and at satellite sites local clinic staff did so. Visual acuity was tested and digital retinal images acquired and graded. Participants were offered rescreening at or before 12-months based on baseline results. RESULTS: In total 203 adults with diabetes attending Indigenous primary care clinics were screened, with divergent results based on the recruitment methods. At the main clinic 135 of 172 eligible adults (79%) were screened. At the satellite sites, 15 of 85 (18%) and 21 of 77 (27%) diabetes patients were screened. Combined coverage 51%. CONCLUSION: A credentialed nurse-educator implemented a model of retinal image-based diabetes education, measured eye screening coverage and adherence to national eye screening guidelines, met the 'acceptable 75% eye screening coverage' benchmark and improved patient eye screening guideline adherence at the one site where the nurse-educator had access to patient recruitment and scheduling. IMPACT: This novel nurse-led primary care iDEES model of retinal image-based diabetes education can improve the currently low Indigenous diabetes eye screening coverage in Australia. Importantly, the nurse-managed iDEES model of integrated diabetes care is readily adaptable to other settings and populations where access to and/or uptake of eye care is suboptimal. CLINICAL TRIAL REGISTRATION: ANZCTRN1261800120435.
Asunto(s)
Diabetes Mellitus , Retinopatía Diabética , Adulto , Australia , Diabetes Mellitus/diagnóstico , Retinopatía Diabética/diagnóstico , Humanos , Tamizaje Masivo , Rol de la Enfermera , Atención Primaria de SaludRESUMEN
OBJECTIVE: To examine the extent to which the Sexuality and Gender Identity Conversion Practices Act 2020 (ACT) and Change or Suppression (Conversion) Practices Prohibition Act 2021 (Vic) might pose a risk to evidence-based and clinically appropriate practice. METHOD: Using a recent publication by Parkinson and Morris as a starting point, the provisions of the new legislation are carefully examined. RESULTS: The ACT and Victorian laws do not imperil psychiatrists undertaking evidence-based and clinically appropriate practice. CONCLUSIONS: While it may be wise for psychiatrists to abandon this area of practice if they hold strong personal beliefs that the failure to identify with one's natal gender is morally wrong, nothing in the new laws should deter psychiatrists from providing people with gender dysphoria with evidence-based and clinically appropriate care.
Asunto(s)
Disforia de Género , Psiquiatría , Femenino , Identidad de Género , Humanos , Masculino , Conducta Sexual , SexualidadRESUMEN
Pseudoisocytosine (J), a neutral analogue of protonated cytosine, is currently the gold standard modified nucleobase in peptide nucleic acids (PNAs) for the formation of J·G-C triplets that are stable at physiological pH. This study shows that triple-helical recognition of RNA and DNA is significantly improved by using 2-aminopyridine (M) instead of J. The positively charged M forms 3-fold stronger M+·G-C triplets than J with uncompromised sequence selectivity. Replacement of six Js with Ms in a PNA 9-mer increased its binding affinity by â¼2 orders of magnitude. M-modified PNAs prefer binding double-stranded RNA over DNA and disfavor off-target binding to single-stranded nucleic acids. Taken together, the results show that M is a promising modified nucleobase that significantly improves triplex-forming PNAs and may provide breakthrough developments for therapeutic and biotechnology applications.
Asunto(s)
Aminopiridinas/química , Conformación de Ácido Nucleico/efectos de los fármacos , Ácidos Nucleicos de Péptidos/metabolismo , Aminopiridinas/metabolismo , Citosina/análogos & derivados , Citosina/química , ADN/química , ADN/metabolismo , ARN BicatenarioRESUMEN
BACKGROUND: The authors previously reported the results of the nonpancreatic neuroendocrine neoplasm cohort of the SWOG S1609 DART (Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors) trial, which permitted all histologic grades and had a 44% overall response rate (ORR) among patients with high-grade disease. Here they sought to validate their findings in a dedicated prospective cohort of high-grade neuroendocrine neoplasms within S1609. METHODS: A prospective, open-label, multicenter, phase 2 clinical trial of ipilimumab plus nivolumab was conducted across multiple rare tumor cohorts. The dedicated, high-grade neuroendocrine neoplasm cohort was examined here. The primary end point was the ORR according to version 1.1 of the Response Evaluation Criteria in Solid Tumors. Secondary end points included progression-free survival (PFS), overall survival (OS), and toxicity. RESULTS: Nineteen patients with high-grade neuroendocrine neoplasms (defined by local pathology review) were enrolled in this cohort of S1609. The most common primary sites were unknown primaries (21%), which were followed by the rectum, gastroesophageal junction, cervix, and pancreas (11%). The median number of lines of prior therapy was 1 (range, 0-3). All patients were microsatellite-stable. The median Ki-67 value was 80%. The ORR was 26% (95% confidence interval [CI], 11%-45%), and the clinical benefit rate (stable disease for ≥6 months plus partial responses plus complete responses) was 32% (95% CI, 13%-57%). The 6-month PFS rate was 32% (95% CI, 16%-61%) with a median PFS of 2.0 months (95% CI, 1.8 months to ∞) and a median OS of 8.7 months (95% CI, 6.1 months to ∞). The most common toxicities were fatigue (32%) and rash (26%), and the most common grade 3/4 immune-related adverse event was rash (15%); there were no events that required treatment discontinuation and no grade 5 events. CONCLUSIONS: Ipilimumab plus nivolumab demonstrated a 26% ORR in patients with high-grade neuroendocrine neoplasms, with durable responses seen in patients with refractory disease.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Tumores Neuroendocrinos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Femenino , Humanos , Ipilimumab/uso terapéutico , Tumores Neuroendocrinos/tratamiento farmacológico , Tumores Neuroendocrinos/patología , Nivolumab/uso terapéutico , Estudios ProspectivosRESUMEN
BACKGROUND: Systemic therapy (ST) can be deferred in patients who have metastatic renal cell carcinoma (mRCC) and slow-growing metastases. Currently, this subset of patients managed with active surveillance (AS) is not well described in the literature. METHODS: This was a prospective observational study of patients with mRCC across 46 US community and academic centers. The objective was to describe baseline characteristics and demographics of patients with mRCC initially managed by AS, reasons for AS, and patient outcomes. Descriptive statistics were used to characterize demographics, baseline characteristics, and patient-related outcomes. Wilcoxon 2-sample rank-sum tests and χ2 tests were used to assess differences between ST and AS cohorts in continuous and categorical variables, respectively. Kaplan-Meier survival curves were used to assess survival. RESULTS: Of 504 patients, mRCC was initially managed by AS (n = 143) or ST (n = 305); 56 patients were excluded from the analysis. Disease was present in 69% of patients who received AS, whereas the remaining 31% had no evidence of disease. At data cutoff, 72 of 143 patients (50%) in the AS cohort had not received ST. The median overall survival was not reached (95% CI, 122 months to not estimable) in patients who received AS versus 30 months (95% CI, 25-44 months) in those who received ST. Quality of life at baseline was significantly better in patients who were managed with AS versus ST. CONCLUSIONS: AS occurs frequently (32%) in real-world clinical practice and appears to be a safe and appropriate alternative to immediate ST in selected patients.
Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Carcinoma de Células Renales/patología , Humanos , Neoplasias Renales/patología , Calidad de Vida , Estudios Retrospectivos , Resultado del Tratamiento , Espera VigilanteRESUMEN
BACKGROUND: Diabetic retinopathy (DR) prevalence is higher in Indigenous Australians than in other Australians and is a major cause of vision loss. Consequently, timely screening and treatment is paramount, and annual eye screening is recommended for Indigenous Australians. AIMS: To assess the prevalence of DR, reduced vision and DR treatment coverage among Indigenous Australian adults with diabetes attending Top End indigenous primary care health services. METHODS: A cross-sectional DR screening study conducted from November 2013 to December 2015 in two very remote Northern Territory Aboriginal primary healthcare services. RESULTS: In 287 subjects, the prevalence of non-proliferative DR, proliferative DR and clinically significant diabetic macular oedema was 37.3%, 5.4% and 9.0% respectively. Treatment coverage for PDR was 60% (of 10 patients) and for CSMO was 17% (of 23 patients). Vision data were available from 122 participants at one site. The proportion with normal vision, reduced vision, impaired vision and blindness was 31.1%, 52.5%, 15.6% and 0.8% respectively. Overall, ungradable monocular image sets (46%) were associated with poorer quality images and missing protocol images (both P < 0.001). Ungradable images for DR were associated with presence of small pupils/media opacities (P < 0.001). Ungradable images for diabetic macular oedema were associated with poorer image quality (P < 0.001), cataracts (P < 0.001) and small pupils (P = 0.04). CONCLUSIONS: A high prevalence of DR, CSMO and impaired vision was noted in Indigenous Australians with diabetes. Screening in primary care is feasible, but more effective screening methods are needed.
Asunto(s)
Diabetes Mellitus , Retinopatía Diabética , Baja Visión , Australia/epidemiología , Estudios Transversales , Retinopatía Diabética/diagnóstico , Retinopatía Diabética/epidemiología , Retinopatía Diabética/terapia , Humanos , Tamizaje Masivo , Prevalencia , Atención Primaria de SaludRESUMEN
AIMS: To improve diabetes management in Indigenous Australians using an integrated nurse-led model of diabetes education and eye screening in indigenous primary care and specialist diabetes clinics. DESIGN: A pre-post study. METHODS: This study will be implemented in indigenous primary care and specialist diabetes clinics in Victoria, Australia. Participants recruited to the study will be existing adult patient with diagnosed diabetes attending study sites. A nurse-credentialled diabetes educator and certified retinal imager will deliver three study components: (a) retinal photography as a diabetic retinopathy screening and patient engagement tool; (b) lifestyle and behaviour surveys, administered at baseline and at the final visit, in 12 months. Findings from the surveys and participants' retinal images will be used to guide; and (c) personalized diabetes education. The primary outcomes are participant adherence to diabetic eye screening recommendations and health service diabetic retinopathy screening coverage. Secondary outcomes are baseline DR prevalence and changes in clinical and lifestyle risk factor levels, diabetes knowledge and satisfaction with diabetes care. DISCUSSION: Compared with non-indigenous Australians, Indigenous Australians have a high prevalence of diabetic retinopathy and blindness, low adherence to eye screening recommendations and suboptimal health literacy. Nurse-credentialled diabetes educators can be trained to incorporate retinal imaging and eye screening into their clinical practice to give image-based diabetes education to facilitate diabetic retinopathy management. IMPACT: Credentialled nurse diabetes educators who integrate eye screening and diabetes education can facilitate timelier diabetic retinopathy screening, referral pathways and treatment of sight-threatening retinopathy. We believe that this model of integrated diabetes education and eye screening will also improve adherence to eye screening recommendations, population screening coverage, health literacy, risk factor levels and diabetes self-care. CLINICAL TRIAL REGISTRATION: ANZCTRN1261800120435.