Structure-Activity Relationships of the Fentanyl Scaffold: Identification of Antagonists as Potential Opioid Overdose Reversal Agents.

Opioid-related overdoses account for almost half of all drug overdose deaths in the United States and cause more preventable deaths every year than car crashes. Fentanyl, a highly potent mu opioid receptor (MOR) agonist and its analogues (fentalogues) are increasingly found in illicit drug samples, both where the primary drug of abuse is an opioid and where it is not. The prevalence of fentalogues in the illicit drug market is thought to be the primary driver of the increased number of opioid-related overdose deaths since 2016. In fact, fentanyl and its analogues are involved in more than 70% of opioid-related overdoses. The standard opioid overdose rescue therapy naloxone is often insufficient to reverse opioid overdoses caused by fentalogue agonists under current treatment paradigms. However, the pharmacology of many fentalogues is unknown. Moreover, within the fentalogue series of compounds, it is possible that antagonists could be identified that might be superior to naloxone as opioid overdose reversal agents. In this report, we explore the pharmacology of 70 fentalogues and identify compounds that behave as MOR antagonists in vitro and demonstrate with one of these reversals of fentanyl-induced respiratory depression in the mouse. Such compounds could provide leads for the development of effective agents for the reversal of opioid overdose.

Opioid Antagonists from the Orvinol Series as Potential Reversal Agents for Opioid Overdose.

The opioid crisis continues to claim many lives, with a particular issue being the ready availability and use (whether intentional or accidental) of fentanyl and fentanyl analogues. Fentanyl is both potent and longer-acting than naloxone, the standard of care for overdose reversal, making it especially deadly. Consequently, there is interest in opioid reversal agents that are better able to counter its effects. The orvinol series of ligands are known for their high-affinity binding to opioid receptors and often extended duration of action; generally, compounds on this scaffold show agonist activity at the kappa and the mu-opioid receptor. Diprenorphine is an unusual member of this series being an antagonist at mu and only a partial agonist at kappa-opioid receptors. In this study, an orvinol antagonist, 14, was designed and synthesized that shows no agonist activity in vitro and is at least as good as naloxone at reversing the effects of mu-opioid receptor agonists in vivo.

Colorectal cancer in an Eastern Caribbean nation: are we missing an opportunity for secondary prevention?

Objective: To establish whether there was any difference in disease stage in patients with screening-detected colorectal cancer (CRC) in a Caribbean country. Methods: The mode of presentation (elective vs. emergent), method of diagnosis (screening vs. symptomatic), and disease stage were retrospectively compared in all consecutive patients who had resections for CRC over a five-year period. Early CRC was defined as disease that could be completely resected with no involvement of adjacent organs, lymph nodes, or distant sites. Locally advanced CRC was disease that involved contiguous organs without distant metastases that was still amenable to curative resection. Results: There were 97 patients at a mean age of 64.9 ± 12.2 years treated for CRC, and only 21 (21.6%) had their diagnoses made through screening. Significantly more screening-detected lesions were early-stage CRCs (21.7% vs. 9.3%; p < 0.001). At the time of diagnosis, patients who did not have screening-detected lesions had a greater proportion of locally advanced (42.3% vs. 0) and metastatic (26.8% vs. 0) CRC. Those who did not have screening-detected lesions had a greater incidence of emergency presentations at diagnosis (26.8% vs. 0). Conclusions: The incidence of screening-detected CRC in this Caribbean nation was low. Consequently, most patients presented with locally advanced or metastatic CRC, for which there is less opportunity to achieve a cure. Significantly more screening-detected lesions were early-stage CRCs. It is time for policymakers to develop a national CRC screening program.

Colorectal cancer in an Eastern Caribbean nation: are we missing an opportunity for secondary prevention?

[ABSTRACT]. Objective. To establish whether there was any difference in disease stage in patients with screening-detected colorectal cancer (CRC) in a Caribbean country. Methods. The mode of presentation (elective vs. emergent), method of diagnosis (screening vs. symptomatic), and disease stage were retrospectively compared in all consecutive patients who had resections for CRC over a five-year period. Early CRC was defined as disease that could be completely resected with no involvement of adjacent organs, lymph nodes, or distant sites. Locally advanced CRC was disease that involved contiguous organs without distant metastases that was still amenable to curative resection. Results. There were 97 patients at a mean age of 64.9 ± 12.2 years treated for CRC, and only 21 (21.6%) had their diagnoses made through screening. Significantly more screening-detected lesions were early-stage CRCs (21.7% vs. 9.3%; p < 0.001). At the time of diagnosis, patients who did not have screening-detected lesions had a greater proportion of locally advanced (42.3% vs. 0) and metastatic (26.8% vs. 0) CRC. Those who did not have screening-detected lesions had a greater incidence of emergency presentations at diagnosis (26.8% vs. 0). Conclusions. The incidence of screening-detected CRC in this Caribbean nation was low. Consequently, most patients presented with locally advanced or metastatic CRC, for which there is less opportunity to achieve a cure. Significantly more screening-detected lesions were early-stage CRCs. It is time for policymakers to develop a national CRC screening program.

[RESUMEN]. Objetivo. Determinar las diferencias en el estadio de la enfermedad en pacientes con cáncer colorrectal diagnosticado mediante un programa de detección sistemática en un país del Caribe. Métodos. Se realizó una comparación en retrospectiva de la modalidad de presentación (programada o de urgencia), el método de diagnóstico (por detección sistemática o por síntomas) y el estadio de la enfermedad en todos los pacientes consecutivos con resecciones por cáncer colorrectal en un período de cinco años. Se definió el cáncer colorrectal en fase inicial o incipiente como una enfermedad que puede extirparse completamente sin la afectación de los órganos adyacentes, los ganglios linfáticos o focos distantes. Se consideró el cáncer colorrectal localmente avanzado como una enfermedad que afecta a los órganos contiguos sin metástasis a distancia y aún susceptible de resección curativa. Resultados. Hubo 97 pacientes de una media de edad de 64,9 ± 12,2 años en tratamiento por cáncer colorrectal y únicamente 21 (21,6%) habían recibido un diagnóstico mediante un programa de detección sistemática. Un número significativamente mayor de los diagnósticos dados por detección sistemática se trató de cáncer colorrectal de fase inicial (21,7 % frente a 9,3 %; p < 0,001). En el momento del diagnóstico, se registró una mayor proporción de cáncer colorrectal localmente avanzado (42,3 % frente a 0) y metastásico (26,8 % frente a 0) en los pacientes sin lesiones diagnosticadas en un programa de detección sistemática. Los pacientes cuyas lesiones no fueron diagnosticadas mediante la detección sistemática registraron una mayor incidencia de presentaciones de urgencia en el momento del diagnóstico (26,8 % frente a 0). Conclusiones. La incidencia de cáncer colorrectal diagnosticado mediante detección sistemática en este país del Caribe fue baja. En consecuencia, la mayoría de los pacientes presentó cáncer colorrectal localmente avanzado o metastásico, cuya oportunidad de cura es menor. Un número significativamente mayor de lesiones diagnosticadas mediante detección sistemática se trató de cáncer colorrectal de fase inicial. Ha llegado el momento de que las personas responsables de las políticas elaboren un programa nacional de detección sistemática de cáncer colorrectal.

[RESUMO]. Objetivo. Determinar se houve diferença no estágio da doença detectada no exame de prevenção de câncer colorretal em um país do Caribe. Métodos. Fatores como tipo de apresentação (eletiva vs. de emergência), método de diagnóstico (prevenção vs. detecção sintomática) e estágio da doença foram comparados retrospectivamente em todos os pacientes consecutivos submetidos a cirurgia de ressecção de câncer colorretal em um período de cinco anos. Definiu-se doença em estágio inicial como o tumor passível de ressecção total sem o envolvimento de órgãos adjacentes, gânglios linfáticos ou sítios a distância, e doença localmente avançada como o tumor envolvendo órgãos contíguos, sem metástase a distância, mas passível de resseção curativa. Resultados. Noventa e sete pacientes com média de idade de 64,9 ± 12,2 anos foram tratados devido ao câncer colorretal e apenas 21 (21,6%) tiveram a doença diagnosticada no exame de prevenção. Um percentual significativamente maior de lesões detectadas no exame de prevenção estava em estágio inicial (21,7% vs. 9,3%; p < 0.001). No momento do diagnóstico, os pacientes cujas lesões de câncer colorretal não foram detectadas com o exame de prevenção apresentaram um maior percentual de doença localmente avançada (42,3% vs. 0) ou metastática (26,8% vs. 0). Houve também, entre esses pacientes, uma maior incidência de apresentação em caráter de emergência (26,8% vs. 0). Conclusões. Observou-se uma baixa incidência de câncer colorretal na população deste país do Caribe. Porém, a maioria dos pacientes apresentou doença localmente avançada ou metastática no diagnóstico – uma situação associada a uma menor chance de cura. O percentual de lesões detectadas em estágio inicial com o exame de prevenção foi significativamente maior. As autoridades de saúde devem aproveitar a oportunidade e instituir um programa nacional de prevenção do câncer colorretal.

Colorectal cancer in an Eastern Caribbean nation: are we missing an opportunity for secondary prevention? / El cáncer colorrectal en un país del Caribe oriental: ¿estamos desaprovechando una oportunidad de prevención secundaria? / Câncer colorretal em um país do Caribe Oriental: estamos deixando passar a oportunidade de realizar a prevenção secundária?

ABSTRACT Objective. To establish whether there was any difference in disease stage in patients with screening-detected colorectal cancer (CRC) in a Caribbean country. Methods. The mode of presentation (elective vs. emergent), method of diagnosis (screening vs. symptomatic), and disease stage were retrospectively compared in all consecutive patients who had resections for CRC over a five-year period. Early CRC was defined as disease that could be completely resected with no involvement of adjacent organs, lymph nodes, or distant sites. Locally advanced CRC was disease that involved contiguous organs without distant metastases that was still amenable to curative resection. Results. There were 97 patients at a mean age of 64.9 ± 12.2 years treated for CRC, and only 21 (21.6%) had their diagnoses made through screening. Significantly more screening-detected lesions were early-stage CRCs (21.7% vs. 9.3%; p < 0.001). At the time of diagnosis, patients who did not have screening-detected lesions had a greater proportion of locally advanced (42.3% vs. 0) and metastatic (26.8% vs. 0) CRC. Those who did not have screening-detected lesions had a greater incidence of emergency presentations at diagnosis (26.8% vs. 0). Conclusions. The incidence of screening-detected CRC in this Caribbean nation was low. Consequently, most patients presented with locally advanced or metastatic CRC, for which there is less opportunity to achieve a cure. Significantly more screening-detected lesions were early-stage CRCs. It is time for policymakers to develop a national CRC screening program.

RESUMEN Objetivo. Determinar las diferencias en el estadio de la enfermedad en pacientes con cáncer colorrectal diagnosticado mediante un programa de detección sistemática en un país del Caribe. Métodos. Se realizó una comparación en retrospectiva de la modalidad de presentación (programada o de urgencia), el método de diagnóstico (por detección sistemática o por síntomas) y el estadio de la enfermedad en todos los pacientes consecutivos con resecciones por cáncer colorrectal en un período de cinco años. Se definió el cáncer colorrectal en fase inicial o incipiente como una enfermedad que puede extirparse completamente sin la afectación de los órganos adyacentes, los ganglios linfáticos o focos distantes. Se consideró el cáncer colorrectal localmente avanzado como una enfermedad que afecta a los órganos contiguos sin metástasis a distancia y aún susceptible de resección curativa. Resultados. Hubo 97 pacientes de una media de edad de 64,9 ± 12,2 años en tratamiento por cáncer colorrectal y únicamente 21 (21,6%) habían recibido un diagnóstico mediante un programa de detección sistemática. Un número significativamente mayor de los diagnósticos dados por detección sistemática se trató de cáncer colorrectal de fase inicial (21,7 % frente a 9,3 %; p < 0,001). En el momento del diagnóstico, se registró una mayor proporción de cáncer colorrectal localmente avanzado (42,3 % frente a 0) y metastásico (26,8 % frente a 0) en los pacientes sin lesiones diagnosticadas en un programa de detección sistemática. Los pacientes cuyas lesiones no fueron diagnosticadas mediante la detección sistemática registraron una mayor incidencia de presentaciones de urgencia en el momento del diagnóstico (26,8 % frente a 0). Conclusiones. La incidencia de cáncer colorrectal diagnosticado mediante detección sistemática en este país del Caribe fue baja. En consecuencia, la mayoría de los pacientes presentó cáncer colorrectal localmente avanzado o metastásico, cuya oportunidad de cura es menor. Un número significativamente mayor de lesiones diagnosticadas mediante detección sistemática se trató de cáncer colorrectal de fase inicial. Ha llegado el momento de que las personas responsables de las políticas elaboren un programa nacional de detección sistemática de cáncer colorrectal.

RESUMO Objetivo. Determinar se houve diferença no estágio da doença detectada no exame de prevenção de câncer colorretal em um país do Caribe. Métodos. Fatores como tipo de apresentação (eletiva vs. de emergência), método de diagnóstico (prevenção vs. detecção sintomática) e estágio da doença foram comparados retrospectivamente em todos os pacientes consecutivos submetidos a cirurgia de ressecção de câncer colorretal em um período de cinco anos. Definiu-se doença em estágio inicial como o tumor passível de ressecção total sem o envolvimento de órgãos adjacentes, gânglios linfáticos ou sítios a distância, e doença localmente avançada como o tumor envolvendo órgãos contíguos, sem metástase a distância, mas passível de resseção curativa. Resultados. Noventa e sete pacientes com média de idade de 64,9 ± 12,2 anos foram tratados devido ao câncer colorretal e apenas 21 (21,6%) tiveram a doença diagnosticada no exame de prevenção. Um percentual significativamente maior de lesões detectadas no exame de prevenção estava em estágio inicial (21,7% vs. 9,3%; p < 0.001). No momento do diagnóstico, os pacientes cujas lesões de câncer colorretal não foram detectadas com o exame de prevenção apresentaram um maior percentual de doença localmente avançada (42,3% vs. 0) ou metastática (26,8% vs. 0). Houve também, entre esses pacientes, uma maior incidência de apresentação em caráter de emergência (26,8% vs. 0). Conclusões. Observou-se uma baixa incidência de câncer colorretal na população deste país do Caribe. Porém, a maioria dos pacientes apresentou doença localmente avançada ou metastática no diagnóstico - uma situação associada a uma menor chance de cura. O percentual de lesões detectadas em estágio inicial com o exame de prevenção foi significativamente maior. As autoridades de saúde devem aproveitar a oportunidade e instituir um programa nacional de prevenção do câncer colorretal.

Epidemiology of colorectal cancer in Barbados: A short report.

Barbados is a Caribbean island with a high incidence of colorectal cancer. This study collected epidemiologic data from Barbadian patients with colorectal cancer. There was an opportunity for targeted screening in patients actively enrolled in clinics for management of chronic diseases, accounting for 72% of cases. We also identified areas of high incidence where resources should be directed in a screening programme.

Colorectal cancer demographics in Barbados.

Barbados is an island in the Eastern Caribbean that is reported to have the 8th highest incidence of colorectal cancer (CRC) worldwide. However, these figures are based only on estimates, and there is little available epidemiological data collected from Barbadians with CRC. The present study sought to collect epidemiologic data from patients in Barbados diagnosed with CRC. This information is considered important to shape national public health policies. For this purpose, hospital admission registers at all tertiary care facilities in Barbados were retrospectively audited over a four-year period from January 1, 2014 to December 31, 2018 to identify patients who underwent operative treatment for CRC. The following data were extracted: Age, sex, ethnicity, the location of the primary tumour and tumour stage. Descriptive statistical analyses were generated using SPSS version 21.0. The results revealed that there were 97 patients with CRC at a mean age of 64.9 years (SD ±12.2) and a male preponderance (1.3:1). The majority (93.8%) were from the African diaspora. Only 18.5% of diagnoses were made at (opportunistic) screening. Consequently, two thirds of the patients had advanced-stage disease at diagnosis. The disease staging of the patients was as follows: Stage 0 (1%), stage I (10.3%), stage II (23.7%), stage III (38.1%) and stage IV (26.8%). Right-sided primary tumours were most common (44.3%), followed by left-sided (41.2%) and rectal lesions (14.4%). Women were significantly more likely to have right-sided lesions (55 vs. 45%) and males were more likely to have rectal lesions (77 vs. 23%). On the whole, the present study highlights the need to implement a national screening programme in this high-risk population of African origin with a predominantly right-sided distribution of CRC primary tumours. This is reinforced by the fact that 10% of patients will be diagnosed before the age of 50 years with more aggressive disease.

Factors Associated with Academic Performance in Physician Assistant Graduate Programs and National Certification Examination Scores. A Literature Review.

PURPOSE: A physician assistant (PA) is a state-licensed, nationally certified healthcare professional who practices medicine on healthcare teams with physicians and other providers. PAs practice medicine across the US (all 50 states, the District of Columbia, and the US territories). In recent years, the demand for clinicians has increased dramatically which has led to an increase in the number of practicing PAs. To meet this growing demand for healthcare providers, identifying applicants capable of overcoming the challenges associated with the PA educational track in addition to the corresponding clinical training is crucial. METHOD: In this paper, we reviewed the literature and discuss preadmission factors and their relationship toward completion of PA graduate programs and successfully passing the national certification examination (PANCE). RESULTS: Previous studies indicated a weak positive association between verbal GRE scores and success on the PANCE. Moreover, undergraduate GPA, and taking a variety of undergraduate science prerequisites correlates with passing the PANCE. DISCUSSION: Investigations of success correlates of other professional programs indicated that psychological factors may have potential for use in predicting whether an applicant would be successful in PA school. These include tests for emotional intelligence and particular personality characteristics.

Considerations for a Primary Care Physician Assistant in Treating Kidney Transplant Recipients.

The escalating amount of kidney transplant recipients (KTRs) represents a significant dilemma for primary care providers. As the number of physician assistants (PAs) has been steadily increasing in primary care in the United States, the utilization of these healthcare professionals presents a solution for the care of post-kidney transplant recipients. A physician assistant (PA) is a state licensed healthcare professional who practices medicine under physician supervision and can alleviate some of the increasing demands for primary patient care. Here we provide an outline of the crucial components and considerations for PAs caring for kidney transplant recipients. These include renal function and routine screenings, drug monitoring (both immunosuppressive and therapeutic), pre-existing and co-existing conditions, immunizations, nutrition, physical activity, infection, cancer, and the patient's emotional well-being. PAs should routinely monitor renal function and blood chemistry of KTRs. Drug monitoring of KTRs is a crucial responsibility of the PA because of the possible side-effects and potential drug-drug interactions. Therefore, PAs should obtain a careful and detailed patient history from KTRs. PAs should be aware of pre- and co-existing conditions of KTRs as this impacts treatment decisions. Regarding immunization, PAs should avoid administering vaccines containing live or attenuated viruses to KTRs. Because obesity following kidney transplantation is associated with decreased allograft survival, PAs should encourage KTRs to maintain a balanced diet with limited sugar. In addition, KTRs should be urged to gradually increase their levels of physical activity over subsequent years following surgery. PAs should be aware that immunosuppressive medications diminish immune defenses and make KTRs more susceptible to bacterial, viral, and fungal infections. Moreover, KTRs should be screened routinely for cancer due to the higher risk of development from immunosuppressive therapy. PAs must remain cognizant of the emotional well-being of the KTR, as many transplant patients struggle with fear, frustration, and acceptance.