A patient with rapidly growing axillary masses.

ABSTRACT: About 85,000 melanomas are diagnosed every year in the United States, but only about 3.2% are diagnosed without a primary site. This article describes a patient who presented with two rapidly growing axillary masses and was found to have metastatic melanoma of the lymph nodes with no known primary site. Melanoma of unknown primary (MUP) site is staged either III or IV level. Management is determined in the same manner as stage-matched melanoma of known primary site.

Optimizing Strategies for Chlamydia trachomatis and Neisseria gonorrhoeae Screening in Men Who Have Sex With Men: A Modeling Study.

BACKGROUND: International guidelines recommend the systematic screening for Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT) infections in all men who have sex with men (MSM) who have engaged in unprotected sex. However, the optimal screening strategy remains unclear. We developed a modeling approach to optimize NG/CT screening strategy in MSM. METHODS: A compartmental model of NG/CT screening and infection was implemented. NG/CT anal, pharyngeal, and urine (APU) samples from MSM attending the sexually transmitted infections clinic were used to estimate the screening rate, prevalence, and incidence in a base case scenario. Different screening strategies (scenarios; S) were then evaluated: APU samples every 12 months (S1); APU samples every 3 months (S2); APU samples every 6 months (S3); anal and pharyngeal (AP) samples every 6 months (S4); and AP samples every 3 months (S5). RESULTS: We analyzed 2973 triplet APU samples from 1255 patients. We observed 485 NG and 379 CT diagnoses. NG/CT prevalence and incidence estimates were 12.0/11.1% and 40/29 per 100 person-years, respectively, in the base case scenario. As compared to S2, the reference strategy, the proportions of missed NG/CT diagnoses were 42.0/41.2% with S1, 21.8/22.5% with S3, 25.6/28.3% with S4, and 6.3/10.5% with S5, respectively. As compared to S2, S1 reduced the cost of the analysis by 74%, S3 by 50%, S4 by 66%, and S5 by 33%. The numbers needed to screen for catching up the missed NG/CT diagnoses were 49/67 with S1, 62/82 with S3, 71/87 with S4, and 143/118 with S5. CONCLUSIONS: S5 appears to be the best strategy, missing only 6.3/10.5% of NG/CT diagnoses, for a cost reduction of 33%.

Sedative-hypnotic initiation and renewal at discharge in hospitalized older patients: an observational study.

BACKGROUND: Sedative-hypnotics (SHs) are widely used in France but there are no available data addressing their prescription specifically in hospitalized older patients. The objective is thus to determine the cumulative incidence of sedative-hypnotic (SH) medications initialized during a hospital stay of older patients, the proportion of SH renewal at discharge among these patients and to study associated risk factors. METHODS: We conducted a retrospective observational study in six internal medicine units and six acute geriatric units in eight hospitals (France). We included 1194 inpatients aged 65 and older without SH medications prior to hospitalization. Data were obtained from patients' electronic pharmaceutical records. Primary outcome was the cumulative incidence of SH initiation in the study units. Secondary outcomes were the proportion of SH renewal at discharge and risk factors for SH initiation and renewal at discharge (patient characteristics, hospital organization). A Cox regression model was used to study risk factors for SH initiation. A mixed effects logistic regression was used to study risk factors for SH renewal at discharge. RESULTS: SH initiation occurred in 21.5% of participants 20 days after admission. SH renewal at discharge occurred in 38.7% of patients who had initiated it during their stay and were discharged home and in 56.0% of patients discharged to rehabilitation facilities. Neither patients' characteristics nor hospital organization patterns was associated with SH initiation. SH initiation after the first six days after admission was associated with a lower risk of SH renewal in patients discharged to rehabilitation facilities (OR = 0.19, 95% CI: [0.04-0.80]). CONCLUSIONS: Hospitalization is a period at risk for SH initiation. The implementation of interventions promoting good use of SHs is thus of first importance in hospitals. Specific attention should be paid to patients discharged to rehabilitation facilities.

Choosing Wisely for apheresis.

The Choosing Wisely campaign has stimulated clinicians to think about the appropriateness of various tests and procedures, compelling physicians to make smarter, safer and more effective choices for high quality patient care and to reduce healthcare cost. The American Society for Apheresis (ASFA) strives to advance apheresis medicine through education, evidence-based practice, research and advocacy. To complement these shared missions, ASFA created a working group, consisting of representatives from the various ASFA committees, to produce recommendations for apheresis medicine that reflect the Choosing Wisely guiding principles. A diverse group of ASFA physician and allied health members reviewed, rated and ranked 9 original draft proposals. Additional revisions and refinements were made prior to external review and adoption of five final recommendations by the ASFA Board of Directors. The ASFA Choosing Wisely recommendations encourage apheresis practitioners, patients and donors to discuss and prioritize best clinical practices that avoid harm and waste while optimizing clinical benefit.

Preclinical impact of bevacizumab on brain and tumor distribution of irinotecan and temozolomide.

Glioblastoma (GBM) is the most common primary malignant brain tumour in adults. Prognosis of GBM patients is poor with median overall survival around 15 months. Temozolomide is the chemotherapeutic agent used in the standard of care of newly diagnosed GBM patients relying on radiotherapy with concurrent chemotherapy followed by chemotherapy alone. Irinotecan has shown some efficacy in recurrent malignant gliomas. Bevacizumab has been combined with irinotecan in the treatment of recurrent GBM and with temozolomide in newly diagnosed GBM. As the efficacy of GBM treatments relies on their brain distribution through the blood brain barrier, the aim of the present preclinical work was to study, in in vivo models, the impact of bevacizumab on brain and tumor distribution of temozolomide and irinotecan. Our results show that bevacizumab pre-treatment was associated with a reduced temozolomide brain distribution in tumor-free mice. In tumor bearing mice, bevacizumab increased temozolomide tumor distribution, although not statistically significant. In both tumor-free and tumor-bearing mice, bevacizumab does not modify brain distribution of irinotecan and its metabolite SN-38. Bevacizumab impacts brain distribution of some anti-tumor drugs and potentially their efficacy in GBM. Further studies are warranted to investigate other therapeutic combination.

Propofol, midazolam, vancomycin and cyclosporine therapeutic drug monitoring in extracorporeal membrane oxygenation circuits primed with whole human blood.

INTRODUCTION: As a result of drug sequestration and increased volume of distribution, the extracorporeal membrane oxygenation (ECMO) procedure might lead to a decrease in drug concentrations during a patient's treatment. The aim of this study was to evaluate sedative, antibiotic and immunosuppressive drug loss in ECMO circuit using ex-vivo and in-vitro experiments. METHODS: Blood concentrations of propofol, midazolam, cyclosporine and vancomycin were measured in an ex-vivo ECMO circuit primed with whole human blood, and compared to controls stored in polypropylene tubes. In vitro experiments were also conducted to further explore the role of temperature, oxygen exposure and polyvinylchloride surfaces on propofol loss in the ECMO circuit. RESULTS: Propofol concentration decreased rapidly; 70% of its baseline concentration was lost after only 30 minutes, and only 11% remained after five hours (P <0.001 for the comparison with control polypropylene tube propofol concentration). Further experiments demonstrated that oxygen exposure and contact with polyvinylchloride tubing were respectively responsible for 70% and 85% of propofol loss after 45 minutes. Midazolam concentration also rapidly decreased in the ECMO circuit, with only 54% and 11% of baseline concentration being detected at 30 minutes and 24 hours respectively (P = 0.01 versus control). Alternatively, cyclosporine concentration remained stable for the five first hours, then decreased to 78% and 73% of the baseline value after 24 hours and 48 hours, (P = 0.35 versus control). Lastly, vancomycin concentration remained stable in the ECMO circuit for the 48-hour experimental protocol. CONCLUSIONS: We observed important losses of propofol and midazolam, while cyclosporine concentration decreased slowly and moderately, and vancomycin concentration remained unchanged in the ex-vivo ECMO circuit primed with whole human blood. These data might help intensive care unit physicians planning clinical trials with a final objective to better adapt doses of these drugs while treating critically ill ECMO patients.

A systematic review of adult admissions to ICUs related to adverse drug events.

Adverse drug events (ADE) may lead to hospital admission, and in some cases admission to an ICU is mandatory. We conducted a systematic review dealing with the incidence of ADE requiring ICU admission in adult patients, the reference population being all ICU admissions. Medline, Embase and Web of Science databases were screened from January 1982 to July 2014, using appropriate key words. Only original articles in English reporting the incidence of ADE requiring ICU admission in adult patients among total ICU admissions were included. Article eligibility was assessed by two independent reviewers, a third being involved in cases of disagreement. All reported characteristics (type of ICU, characteristics of patients, incidence of ADE, severity and preventability, drugs involved, causality) in the selected articles were collected for the review. The quality of studies was independently assessed by two reviewers with a specific score that we developed. A meta-analysis was conducted. Inclusion criteria were fulfilled by 11 studies out of the 4,311 identified in the initial literature search. The median (interquartile) quality score was 0.61 (0.44; 0.69). The reported incidences of ADE requiring ICU admission in adult patients ranged from 0.37 to 27.4%, with an associated mortality rate ranging from 2 to 28.1% and a mean length of stay ranging from 2.3 to 6.4 days. Preventable events accounted for 17.5 to 85.7% of the events. Costs and mechanisms at the root of ADE were investigated in only two and five studies, respectively. The forest plot examining the incidence of ADE requiring ICU admission in adult patients was associated with high heterogeneity (I (2) statistic > 98%), and the shape of the corresponding funnel plot was asymmetric. Heterogeneity across studies concerned many features, including studied populations, events considered, causality assessment methods, definitions of preventability and severity. Despite the heterogeneity of the reports, our review indicates that ICU admission due to ADE is a significant issue that should deserve further interest. The review led us to propose a list of items devoted to the reporting of future studies on ADE requiring ICU admissions.

Are Lists of Potentially Inappropriate Medications Associated with Hospital Readmissions? A Systematic Review.

BACKGROUND: Suboptimal prescribing, including the prescription of potentially inappropriate medications (PIM), is frequent in patients aged 65 years and older. PIMs are associated with adverse drug events, which may lead to hospital admissions and readmissions for the most serious cases. Several tools, known as lists of PIMs, can detect suboptimal prescription. OBJECTIVE: This systematic review aimed to identify which lists of PIMs are associated with hospital readmission of older patients. PATIENTS AND METHODS: MEDLINE, the Cochrane Library, EMBASE, and clinicaltrials.gov were searched for the period from 1 January 1991 up to 12 May 2022 to identify original studies assessing the association between PIMs and hospital readmissions or emergency department (ED) revisits within 30 days of discharge in older patients. This study is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 Checklist, and the risk of bias was assessed with the Newcastle-Ottawa Quality Assessment Scale for Cohort Studies (NOS) and the revised Cochrane risk-of-bias tool for randomized trials (RoB 2). RESULTS: A total of six studies presenting four different lists of PIMs were included. Readmission rates varied from 4.3 to 25.5% and the odds ratio (OR) between PIMs and hospital readmission varied from 0.92 [95% confidence interval (CI) 0.59; 1.42] to 6.48 [95% CI 3.00; 14.00]. Only two studies found a statistically significant association between a list of PIMs and hospital readmission. These two studies used different tools: the Screening Tool of Older Person's Prescriptions (STOPP) and the Screening Tool to Alert Doctors to Right Treatment (START) and a combination of Beers Criteria® and STOPP and START. CONCLUSION: This systematic review shows that the association between list of PIMs and 30-day unplanned readmissions remains unclear and seems dependent on the PIM detection tool. Further studies are needed to clarify this association. PROSPERO registration number CRD42021252107.

Opportunity to monitor immunosuppressive drugs in peripheral blood mononuclear cells: where are we and where are we going?

Immunosuppressive (IS) drugs are now widely used as preventive treatments of allograft rejection in transplantation. Therapeutic drug monitoring (TDM) using trough whole blood concentrations is usually warranted and therapeutic range is recommended to ensure efficacy and prevent toxicity from these drugs. This intensive TDM reduces acute graft rejection but despite this management, the acute rejection rate still remains high in the first two years post-transplantation and few improvements have been made recently to reduce this rate. Moreover, in some patients, acute rejections occur despite adequate trough whole blood IS concentrations. Thus, other ways to monitor immunosuppressive drug effects have to be investigated. As lymphocyte cells are the site of action of IS drugs and so the effect compartment of the drug, monitoring IS drugs in lymphocytes, or for practical reasons in peripheral blood mononuclear cells (PBMC), could be more relevant than standard TDM. The aim of this paper is to review the recent work conducted on the advantages of monitoring IS drugs in PBMC, particularly for calcineurin inhibitors and mammalian target of rapamycin (m-TOR) inhibitors, from an analytical point of view as well as a clinical point of view.

Development of a new UPLC-MSMS method for the determination of temozolomide in mice: application to plasma pharmacokinetics and brain distribution study.

A sensitive and accurate liquid chromatography method with mass spectrometry detection was developed and validated for the quantification of temozolomide in mouse plasma and brain. Theophyllin was used as the internal standard. A single-step protein precipitation was used for plasma and brain sample preparation. The method was validated with respect to selectivity, extraction recovery, linearity, intra- and inter-day precision and accuracy, limit of quantification and stability. The method has a limit of quantification of 50 ng/mL for temozolomide in plasma and 125 ng/g in brain. This method was used successfully to perform brain and plasma pharmacokinetic studies of temozolomide in mice after intraperitoneal administration.

Population pharmacokinetics of everolimus in cardiac recipients: comedications, ABCB1, and CYP3A5 polymorphisms.

BACKGROUND: The aim of this study was, using routine drug monitoring data, to identify patient characteristics that may influence everolimus (EVE) pharmacokinetic parameters and to develop a population pharmacokinetic model to predict EVE whole blood concentrations in cardiac recipients. METHODS: Fifty-nine patients were enrolled in the prospective study. Patient's characteristics were recorded including biological covariates and treatments. CYP3A5 and ABCB1 polymorphisms were determined. Seven hundred seventy-five EVE blood samples were collected for routine drug monitoring. Population pharmacokinetic modeling was carried out using the nonlinear mixed-effects modeling program. Results were analyzed according to a 1-compartment pharmacokinetic model with linear absorption and elimination. The model was evaluated using a bootstrap method and a visual predictive check procedure. RESULTS: The pharmacokinetic of EVE in cardiac recipients was best described by a 1-compartment model. Interindividual variability was best described by an exponential error model and residual error by a proportional plus additive error model. Estimation of EVE apparent clearance (3.33 ± 0.20 L/h) and apparent volume of distribution (146 ± 33 L) were in accordance with previously published data. Bilirubinemia and cyclosporine significantly influenced EVE clearance. Some covariates that were expected to influence EVE clearance, for example, ABCB1 and CYP3A5 polymorphisms, were not evidenced. No covariates influenced the volume of distribution of EVE. CONCLUSIONS: This study is the first population pharmacokinetic model of EVE in heart transplantation patients. It allows a better description of the pharmacokinetics of EVE. The present population pharmacokinetic model allows estimating a priori and a posteriori EVE concentrations in cardiac recipients and could limit the over and under drug exposure in this population.

Impact of extracorporeal membrane oxygenation and continuous venovenous hemodiafiltration on the pharmacokinetics of oseltamivir carboxylate in critically ill patients with pandemic (H1N1) influenza.

PURPOSE: The neuraminidase inhibitor oseltamivir is a recommended treatment for influenza A (H1N1) infection. In rare cases, some patients develop influenza-associated multiple organ failures, requiring rescue therapies such as extracorporeal membrane oxygenation (ECMO) or continuous venovenous hemodiafiltration (CVVHDF). This study was designed to evaluate the impact of ECMO and CVVHDF on the pharmacokinetics of oseltamivir carboxylate (OC) in critically ill patients with pandemic (H1N1) influenza treated with oseltamivir. PATIENTS AND METHODS: Seven critically ill patients on venovenous ECMO for severe pandemic (H1N1) influenza associated with acute respiratory distress syndrome were treated with various doses of oseltamivir (75 or 150 mg twice daily). Because of acute kidney injury, 3 of them also received CVVHDF. OC, the active form of oseltamivir, was quantified in plasma, and main pharmacokinetic parameters were determined. RESULTS: OC Cmax (1029 ± 478 ng/mL) and area under the curve (9.00 ± 4.52 mcg·h/mL) for patients on ECMO with preserved renal function were comparable with those of healthy volunteers or noncritically ill patients. Patients both on ECMO and CVVHDF had 4-to 5-fold higher OC Cmax and area under the curve. CONCLUSIONS: ECMO by itself did not impact on the pharmacokinetics of OC. However, the drug accumulated in the plasma of patients on ECMO who also received CVVHDF for renal failure. Based on these results, we recommend that oseltamivir dosage should be decreased and plasma levels of OC be monitored in patients receiving CVVHDF because of acute kidney injury.

Physician Assistant Program Perseveres Through COVID-19 Pandemic.

ABSTRACT: The COVID-19 pandemic has disrupted almost every aspect of life globally, with higher education one of many direct targets. Institutions and educators have been faced with urgent crises of how to conduct business as usual while maintaining expectations of high standards and uncompromised goals. As physician assistant (PA) educators at Seton Hall University, we rallied and brainstormed approaches to daily instruction to keep students on track and faculty both effective and sane. We tapped technological resources offered by our university, learned countless new skills, and adapted classroom activities to online virtual platforms. Creativity and flexibility became the norm as we modified the way we did everything while remaining laser focused on the ultimate objectives. Our intention was to provide insight, motivation, and, at a minimum, an example of how to do things differently when faced with roadblocks. We were inspired by an editorial by Mary Jo Bondy, DHEd, MHS, PA-C, former CEO of the Physician Assistant Education Association, in which she called for collective innovation, collaboration, publication, and circulation of stories. With that charge, we assembled a detailed account of how a didactic team within our faculty maneuvered the challenges created by COVID-19, in hopes of adding to the arsenal of small triumphs in this uncharted territory.

Safety of Elderly Fallers: Identifying Associated Risk Factors for 30-Day Unplanned Readmissions Using a Clinical Data Warehouse.

BACKGROUND: Hospital readmissions are a major problem in the older people as they are frequent, costly, and life-threatening. Falls among older adults are the leading cause of injury, deaths, and emergency department visits for trauma. OBJECTIVE: The main objective was to determine risk factors associated with a 30-day readmission after index hospital admission for fall-related injuries. METHODS: A retrospective nested case-control study was conducted. Data from elderly patients initially hospitalized for fall-related injuries in 2019, in 11 of the Greater Paris University Hospitals and discharged home, were retrieved from the clinical data warehouse. Cases were admission of elderly patients who subsequently experienced a readmission within 30 days after discharge from the index admission. Controls were admission of elderly patients who were not readmitted to hospital. RESULTS: Among 670 eligible index admissions, 127 (18.9%) were followed by readmission within 30 days after discharge. After multivariate analysis, men sex (odds ratio [OR] = 2.29, 95% confidence interval [CI] = 1.45-3.61), abnormal concentration of C-reactive protein, and anemia (OR = 2.22, 95% CI = 1.28-3.85; OR = 1.85, 95% CI = 1.11-3.11, respectively) were associated with a higher risk of readmission. Oppositely, having a traumatic injury at index admission decreased this risk (OR = 0.47, 95% CI = 0.28-0.81). CONCLUSIONS: Reducing early unplanned readmission is crucial, especially in elderly patients susceptible to falls. Our results indicate that the probability of unplanned readmission is higher for patients with specific characteristics that should be taken into consideration in interventions designed to reduce this burden.

Which Potentially Inappropriate Medications List Can Detect Patients At Risk of Readmissions in the Older Adult Population Admitted for Falls? An Observational Multicentre Study Using a Clinical Data Warehouse.

BACKGROUND AND OBJECTIVE: Hospital readmissions are common in the older adult population and potentially inappropriate medications are known to be involved in these readmissions. Several lists of potentially inappropriate medications have been published in diverse countries in order to adapt the lists to local specificities. Among them, the Beers Criteria® were first published in 1991 in the USA, followed by the French Laroche list, the Norwegian NORGEP criteria, the German PRISCUS list, the Austrian consensus panel list and the European list, EU-7. The main objective was to detect which potentially inappropriate medications list can better detect hospital readmissions within 30 days in the older adult population hospitalised for fall-related injuries. METHODS: We conducted a multicentre, observational, retrospective cohort study. Data from older patients initially hospitalised for falls in 2019 and discharged home were retrieved from the Clinical Data Warehouse. Exposure to potentially inappropriate medications was classified according to the six lists mentioned above. The local ethics committee approved the study protocol (number CER-2020-79). RESULTS: After adjustments using propensity score matching, taking a potentially inappropriate medication as per the Laroche and PRISCUS lists was associated with a 30-day hospital readmission with an odds ratio of 1.58 (95% confidence interval 1.06-2.37) and 1.68 (95% confidence interval 1.13-2.50), respectively, while the other four studied lists showed no associations with readmissions. CONCLUSIONS: Our study evidenced that not all lists published allow the accurate prediction of hospital readmissions to the same extent. We found that the Laroche and PRISCUS lists were associated with increased 30-day all-cause hospital readmissions after an index admission with a fall-related injury.

Qualitative Assessment of Bias and Comfort in Inclusive Sexual History Taking Skills of Physician Assistant Students.

PURPOSE: Sexual history taking is an integral skill for clinicians, as sexual health is a component of a complete medical evaluation. Medical curricula lack effective sexual history instruction, creating gaps in clinicians' confidence and proficiency. Average sexual and gender minority (SGM) curricular inclusion content is 5 hours over a 4-year span. This study investigated how students perceive their comfort level and biases during a simulated sexual history taking encounter. METHODS: Data were derived from student reflection assignments following simulated sexual history interviews. Researchers analyzed and coded data. Themes were labeled and paired with corresponding quotes from data. RESULTS: Comfort and bias were predetermined main themes, each with eight subcategories that emerged including embarrassment, insight, lack of exposure, comfort/discomfort with sexual subject matter, and preparedness. Students' personal perceptions of comfort and biases represented a broad spectrum within the overarching concepts. CONCLUSIONS: Trainee insight can guide educational and instructional modifications on proficient, inclusive sexual history taking. Exercises with sexual history inter¬views inclusive of SGM populations are essential tools to build student comfort with sexual content topics and diminish potential for invasive biases to undermine the integrity of sexual history taking. Future research is necessary, including implementation of pre and post surveys to gauge efficacy of instruction.

Assessment of Good Practice Guidelines for Administration of Drugs via Feeding Tubes by a Clinical Pharmacist in the Intensive Care Unit.

BACKGROUND: In intensive care units, patients are frequently unable to take oral drugs because of orotracheal intubation or sedation. LOCAL PROBLEM: Adverse events occurred during the administration of drugs by feeding tube. This study assessed the impact of implementing good practice guidelines by a clinical pharmacist on the prescription and administration of drugs through feeding tubes. METHODS: Nonconformity of drug prescription and administration in patients with feeding tubes was assessed before and after implementation of good practice guidelines in the intensive care unit of a large teaching hospital. Data were collected from medical records and interviews with physicians and nurses using a standardized form. Assessment of prescription nonconformity included compatibility of a drug's absorption site with the administration route. Assessment of administration nonconformity included the preparation method. RESULTS: The analysis included 288 prescriptions and 80 administrations before implementation and 385 prescriptions and 211 administrations after implementation. Prescriptions in which the drug's absorption site was not compatible with the administration route decreased significantly after implementation (19.8% vs 7.5%, P < .01). Administration nonconformity decreased significantly in regard to crushing tablets and opening capsules (51.2% vs 4.3%, P < .01) and the solvent used (67.1% vs 3.5%, P < .01). Simultaneous mixing of drugs in the same syringe did not decrease significantly (71.2% vs 62.9%, P = .17). CONCLUSION: Implementation of good practice guidelines by a multidisciplinary team in the intensive care unit significantly improved practices for administering crushed, opened, and dissolved oral forms of drugs by feeding tube.