Phase II Randomized Study of Ramucirumab and Pembrolizumab Versus Standard of Care in Advanced Non-Small-Cell Lung Cancer Previously Treated With Immunotherapy-Lung-MAP S1800A.

PURPOSE: Resistance to immune checkpoint inhibition (ICI) in advanced non-small-cell lung cancer (NSCLC) represents a major unmet need. Combining ICI with vascular endothelial growth factor (VEGF)/VEGF receptor inhibition has yielded promising results in multiple tumor types. METHODS: In this randomized phase II Lung-MAP nonmatch substudy (S1800A), patients ineligible for a biomarker-matched substudy with NSCLC previously treated with ICI and platinum-based chemotherapy and progressive disease at least 84 days after initiation of ICI were randomly assigned to receive ramucirumab plus pembrolizumab (RP) or investigator's choice standard of care (SOC: docetaxel/ramucirumab, docetaxel, gemcitabine, and pemetrexed). With a goal of 130 eligible patients, the primary objective was to compare overall survival (OS) using a one-sided 10% level using the better of a standard log-rank (SLR) and weighted log-rank (WLR; G[rho = 0, gamma = 1]) test. Secondary end points included objective response, duration of response, investigator-assessed progression-free survival, and toxicity. RESULTS: Of 166 patients enrolled, 136 were eligible (69 RP; 67 SOC). OS was significantly improved with RP (hazard ratio [80% CI]: 0.69 [0.51 to 0.92]; SLR one-sided P = .05; WLR one-sided P = .15). The median (80% CI) OS was 14.5 (13.9 to 16.1) months for RP and 11.6 (9.9 to 13.0) months for SOC. OS benefit for RP was seen in most subgroups. Investigator-assessed progression-free survival (hazard ratio [80% CI]: 0.86 [0.66 to 1.14]; one-sided SLR, P = .25 and .14 for WLR) and response rates (22% RP v 28% SOC, one-sided P = .19) were similar between arms. Grade ≥ 3 treatment-related adverse events occurred in 42% of patients in the RP group and 60% on SOC. CONCLUSION: This randomized phase II trial demonstrated significantly improved OS with RP compared with SOC in patients with advanced NSCLC previously treated with ICI and chemotherapy. The safety was consistent with known toxicities of both drugs. These data warrant further evaluation.

Interprofessional student-led outreach to high-risk older adults during the COVID-19 pandemic.

In response to a statewide stay-at-home order during the COVID-19 pandemic, the Seniors Clinic launched an interprofessional student-led, telephone-based outreach initiative targeting older adults deemed high risk for social isolation. The initiative primarily aimed to enhance students' geriatric and interprofessional education during a time when clinical learning opportunities were limited, as well as supporting geriatric patients and providers through outreach during the COVID-19 quarantine period. Nurse practitioner, medical, and pharmacy students participated in virtual patient contact, geriatric case-based learning, and team-based interprofessional development. We conducted pre-and post-outreach assessments with students and geriatric providers to determine the effects of this initiative. After participating in the 3-month outreach initiative, interprofessional students reported increased confidence in conducting outreach calls, participating in interdisciplinary team discussions, and reviewing geriatric cases. This student-led telephone-based outreach to older adults improved students' exposure to and confidence with interprofessional teamwork and geriatric medicine. Our experience can inform future interprofessional initiatives to improve outreach to populations affected by public health emergencies.

Tonsillectomy Outcomes for Children With Severe Obesity.

OBJECTIVES/HYPOTHESIS: To determine the success of an adenotonsillectomy (T&A) in treating children with severe obesity utilizing a more accurate obesity scale. STUDY DESIGN: Retrospective cohort. METHODS: A retrospective cohort of children with obesity between 5 and 10 years of age who underwent a T&A at Children's Hospital of Colorado (CHCO) was used. This study also utilized publicly available data from the Childhood Adenotonsillectomy Trial (CHAT) study. The cohort was divided into three obesity classes using age- and sex-specific body mass index (BMI) expressed as a percentage of the 95th percentile (%BMIp95) and compared for operative success differences. RESULTS: There were 132 patients included in our primary analysis, with obesity distribution as follows: Class 1 to 53 patients (40%), Class 2 to 45 patients (34%), and Class 3 to 34 patients (26%). Overall, 52 patients (35.9%) experienced a cure (obstructive apnea/hypopnea index [OAHI] <1), with 27 (52%) patients in Class 1 obesity, 18 (35%) in Class 2, and 7 (13%) in Class 3. Class 3 had a significantly lower obstructive sleep apnea cure rate compared with Class 1 patients (P = .013), but after adjusting for covariates, this difference was no longer present (P > .05). There was no significant difference in the preoperative to postoperative percent change in mean oxygen saturation (P = .82 CHCO, P = .43 CHAT), oxygen nadir (P = .20 CHCO, P = .49 CHAT), or OAHI (P = .12 CHCO, P = .26 CHAT) between the obesity classes. CONCLUSION: After adjusting for covariates, children with Class 3 obesity are as likely to be cured with a T&A as those with Class 1 obesity. A T&A should be considered a first line treatment for all children with obesity. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:461-469, 2022.

Development and Initial Validation of the Lifetime Exposure to Noise and Solvents Questionnaire in U.S. Service Members and Veterans.

Purpose A need exists to investigate the short- and long-term impact of noise exposures during and following military service on auditory health. Currently available questionnaires are limited in their ability to meet this need because of (a) inability to evaluate noise exposures beyond a limited time frame, (b) lack of consensus on scoring, (c) inability to assess impulse exposures (e.g., firearm use), (d) lack of a single questionnaire that assesses both military and nonmilitary exposures, and (e) lack of validity and reliability data. To address these limitations, the Lifetime Exposure to Noise and Solvents Questionnaire (LENS-Q) was developed. The purpose of this report is to describe the development and initial validation of the LENS-Q as a measure of self-reported noise exposure. Method Six hundred ninety participants, consisting of current Service members and recently military-separated (within about 2.5 years) Veterans, completed the LENS-Q, additional study questionnaires, and comprehensive audiometric testing. Noise exposure scores were computed from LENS-Q responses using a simple scoring algorithm that distinguishes between different cumulative levels of exposure and allows for the inclusion of both continuous and impulse noise exposures. Results The LENS-Q demonstrates good construct validity as evidenced by measures of hearing loss, tinnitus, and subjective hearing difficulties all increasing with an increase in noise exposure scores. A logistic regression, adjusting for age and sex, revealed that participants in the highest exposure group were 2.4-3.9 times more likely to experience hearing loss, 2.7-2.8 times more likely to experience tinnitus, and 3.0-3.7 times more likely to report hearing difficulties compared with individuals in the lowest exposure group. Conclusions The LENS-Q captures noise exposure over an individual's lifetime and provides an alternative scoring metric capable of representing exposure to both continuous and impulse noise. Findings suggest that the LENS-Q is a valuable tool for capturing and measuring both military and nonmilitary noise exposure. Supplemental Material https://doi.org/10.23641/asha.14582937.

Feasibility of ambulatory withdrawal management delivered in a NSW drug health service and correlates of completion.

OBJECTIVE: The aim of the present study was to assess short-term ambulatory withdrawal management (AWM) outcomes at a drug health service (DHS) in Sydney, Australia, in the absence of specific funding. METHODS: A clinic file audit review was conducted of patients who commenced AWM at the service during January 2009-June 2011. Successful completion was defined as daily attendance with ≤1 missed day, or transfer onto opioid substitution treatment. RESULTS: Of 110 episodes, 69 (63%) were completed. Median patient age was 35 years (range 18-71 years), and most patients (68%) were male. Patients presented primarily for cannabis (33%) or alcohol (30%) withdrawal, followed by heroin (19%) or other opioids (6%), and benzodiazepines (12%). Completion rates varied from 86% for non-heroin opioids to 31% for benzodiazepines. Older age was associated with increased completion: 76% of those aged >35 years completed compared with 50% of those ≤35 years of age. Only 46% of women who commenced withdrawal management completed compared with 71% of men. CONCLUSIONS Most people commencing AWM at the DHS completed the program, indicating AWM can be performed at public drug and alcohol clinics. Service improvements may help increase completion rates among women and patients withdrawing from benzodiazepines. What is known about the topic? WM is not a standalone treatment for substance dependence, but is commonly a first attempt at treatment. AWM is often more acceptable to patients, and cheaper, than in-patient services. What does this paper add? About two-thirds of patients entering an AWM program operating since 2001 continue to complete the program. What are the implications for practitioners? AWM can be carried out successfully through public drug and alcohol services, although clinic staff support is important.

Individual versus team-based case-management for clients of opioid treatment services: an initial evaluation of what clients prefer.

INTRODUCTION AND AIMS: Case-management is a client-centred intervention to improve the coordination and continuity of delivery of services for people with complex needs. This service has been incorporated into opioid treatment programs in various ways. This study was undertaken to compare two case-management models, termed individual case-management (ICM) and team-based case-management (TBCM). This study aims to describe the new TBCM and client attitudes to, and acceptance of, this model compared with ICM. DESIGN AND METHODS: Clients from two opioid treatment programs, one implementing ICM and one implementing the TBCM, were recruited to undertake a self-complete survey examining satisfaction with case-management during dosing hours over 7 months. Surveys took approximately 10 min to complete. RESULTS: One hundred and sixty-three clients were surveyed (62 ICM, 101 TBCM). Clients were demographically similar, but differed in terms of treatment and drug use characteristics. Significantly higher ratings of case-management were reported from TBCM compared with ICM clients for help with opiate use (P < 0.001), other drug use (P < 0.001), mental health (P < 0.001), accommodation (P = 0.023), relationships/parenting (P = 0.003) and physical health (P = 0.002) and clinic services in terms of fairness and consistency, safety, respect, staff quality and confidentiality (P < 0.001). Compared with ICM clients, TBCM clients were more likely to report ease of access to case-management (P < 0.001), wait significantly less time to see a case-manager (38% vs. 7% seen same day) and 93% and 47% of clients, respectively, reported satisfaction with treatment (P < 0.001). DISCUSSION AND CONCLUSIONS: These initial data indicate client acceptance and satisfaction with the TBCM model. Further evaluation of the model, including cost-effectiveness, is warranted.

Implantation of c-mycER TAM immortalized human mesencephalic-derived clonal cell lines ameliorates behavior dysfunction in a rat model of Parkinson's disease.

Human neural stem cells offer the hope that a cell therapy treatment for Parkinson's disease (PD) could be made widely available. In this study, we describe two clonal human neural cell lines, derived from two different 10-week-old fetal mesencephalic tissues and immortalized with the c-mycER(TAM) transgene. Under the growth control of 4-hydroxytamoxifen, both cell lines display stable long-term growth in culture with a normal karyotype. In vitro, these nestin-positive cells are able to differentiate into tyrosine hydroxylase (TH)-positive neurons and are multipotential. Implantation of the undifferentiated cells into the 6-OHDA substantia nigral lesioned rat model displayed sustained improvements in a number of behavioral tests compared with noncell-implanted, vehicle-injected controls over the course of 6 months. Histological analysis of the brains showed survival of the implanted cells but no evidence of differentiation into TH-positive neurons. An average increase of approximately 26% in host TH immunoreactivity in the lesioned dorsal striatum was observed in the cell-treated groups compared to controls, with no difference in loss of TH cell bodies in the lesioned substantia nigra. Further analysis of the cell lines identified a number of expressed trophic factors, providing a plausible explanation for the effects observed in vivo. The exact mechanisms by which the implanted human neural cell lines provide behavioral improvements in the PD model are not completely understood; however, these findings provide evidence that cell therapy can be a potent treatment for PD acting through a mechanism independent of dopaminergic neuronal cell replacement.

Management of acute pain in methadone maintenance therapy in-patients.

Methadone maintained treatment (MMT) patients may be given less opioid analgesia for acute pain than the general patient, due to requests for analgesia being misinterpreted as craving for drugs. Pain studies have showed that MMT patients have hyperalgesic responses and that cross-tolerance to opioids may be present, suggesting that they may need more analgesia than the non-MMT patient. This study compares the pain management of MMT patients and controls during an acute hospital stay. It is a retrospective study of MMT in-patients and controls matched for medical condition, age and gender, comparing the analgesia given and pain stated in hospital notes. Patients with a chronic pain condition were excluded. MMT patients and controls did not differ in relation to median morphine dose received or average number of pain reports per day, and only a small proportion of both groups engaged in drug-seeking behaviour. Behavioural problems were significantly more common among MMT patients (39% versus 5%, p < 0.001). The fact that the opioid doses were not significantly different between subjects and controls seems to contradict the experimental evidence that patients on methadone tend to be hyperalgesic. Alternatively, MMT patients may be hyperalgesic, and statistically equal levels of opioid analgesia given to both groups may indicate an effective under-treatment of pain in the hyperalgesic MMT group. Inadequate analgesia may contribute to both behavioural problems and premature discharge. Resolving these uncertainties will require prospective studies.

Differential development of neuronal physiological responsiveness in two human neural stem cell lines.

BACKGROUND: Neural stem cells (NSCs) are powerful research tools for the design and discovery of new approaches to neurodegenerative disease. Overexpression of the myc family transcription factors in human primary cells from developing cortex and mesencephalon has produced two stable multipotential NSC lines (ReNcell VM and CX) that can be continuously expanded in monolayer culture. RESULTS: In the undifferentiated state, both ReNcell VM and CX are nestin positive and have resting membrane potentials of around -60 mV but do not display any voltage-activated conductances. As initially hypothesized, using standard methods (stdD) for differentiation, both cell lines can form neurons, astrocytes and oligodendrocytes according to immunohistological characteristics. However it became clear that this was not true for electrophysiological features which designate neurons, such as the firing of action potentials. We have thus developed a new differentiation protocol, designated 'pre-aggregation differentiation' (preD) which appears to favor development of electrophysiologically functional neurons and to lead to an increase in dopaminergic neurons in the ReNcell VM line. In contrast, the protocol used had little effect on the differentiation of ReNcell CX in which dopaminergic differentiation was not observed. Moreover, after a week of differentiation with the preD protocol, 100% of ReNcell VM featured TTX-sensitive Na+-channels and fired action potentials, compared to 25% after stdD. Currents via other voltage-gated channels did not appear to depend on the differentiation protocol. ReNcell CX did not display the same electrophysiological properties as the VM line, generating voltage-dependant K+ currents but no Na+ currents or action potentials under either stdD or preD differentiation. CONCLUSION: These data demonstrate that overexpression of myc in NSCs can be used to generate electrophysiologically active neurons in culture. Development of a functional neuronal phenotype may be dependent on parameters of isolation and differentiation of the cell lines, indicating that not all human NSCs are functionally equivalent.

Assessment of adherence to antiviral therapy in HIV-infected children using the Medication Event Monitoring System, pharmacy refill, provider assessment, caregiver self-report, and appointment keeping.

The authors sought to assess the utility of the electronic Medication Event Monitoring System (MEMS) in monitoring adherence to highly active antiretroviral therapy (HAART) in HIV-infected children and to compare this with other methods of adherence assessment. Twenty-six perinatally HIV-infected children being treated with three or more antiretroviral medications and their caregivers were enrolled and prospectively followed-up for 6 months. Adherence was assessed using MEMS monitoring of one antiretroviral, pharmacy refill records of all antiretrovirals, a caregiver self-report interview, a physician/nurse questionnaire, and appointment-keeping behavior. Viral loads measured at the end of the 6-month period were compared with the various adherence assessment methods. Adherence rates for the MEMS-monitored medication ranged from 12.7% to 97.9% (median = 81.4%), and 11 of the participants (42%) had less than 80% adherence using this method. A MEMS adherence rate greater than 80% was associated with viral load below the threshold of detection 6 months after enrollment (p <.001). Although not as robust, pharmacy refill rates for all antiretroviral medications were also associated with virologic response. The highest specificity was attained when both MEMS and pharmacy refill were used in combination. Physician assessment of adherence rate as well as appointment-keeping behavior was associated with virologic response, whereas caregiver self-report was not.

Enhanced platelet force development despite drug-induced inhibition of platelet aggregation in patients with thromboangiitis obliterans--two case reports.

Thromboangiitis obliterans (TAO) is a nonatherosclerotic, nonnecrotizing, nonspecific, segmental inflammatory obliterative vasculitis, characterized by decreased flow to the distal extremities and increased risk of amputation. While smoking cessation is viewed as critical to successful treatment, various therapeutic options have been employed. While many treatment regimens seek to diminish platelet function, there are relatively few studies of platelet function in this disease entity and even fewer that have offered evidence of increased platelet activity. The authors report here 2 cases of TAO in which evaluations for hypercoagulable states and of platelet function were performed. Platelet contractile force (PCF) was found to be 82% higher than a normal control in 1 TAO patient and 340% higher than normal in the second patient. This was true despite the fact that platelet aggregations confirmed suppression of aggregation by antiplatelet medications. Elevated PCF has been seen in a variety of conditions, such as coronary artery disease and diabetes mellitus, in which endothelial function is abnormal. Whether high PCF values play a role in the pathogenesis of these diseases or simply serve as markers of enhanced platelet function and/or endothelial dysfunction awaits additional evaluations.