Addressing out-of-hospital cardiac arrest with current technology advances: Breaking the deadlock with a mobile network.

Out-of-hospital cardiac arrest (OHCA) is a global public health problem, with survival rates remaining low at around 10% or less despite widespread cardiopulmonary resuscitation (CPR) training and availability of automated external defibrillators (AEDs). This is partly due to the challenges of knowing when and where a sudden OHCA occurs and where the nearest AED is located. In response, countries around the world have begun to use network technology-based smartphone applications. These applications are activated by emergency medical service dispatchers and alert preregistered volunteer first responders (VFRs) to nearby OHCAs using Global Positioning System localization. Accumulating evidence, although mostly from observational studies, shows their effectiveness in increasing the rate of bystander CPR, defibrillation, and patient survival. Current guidelines recommend the use of these VFR alerting systems, and the results of ongoing randomized trials are awaited for further dissemination. This article also proposed the concept of a life-saving mobile network (LMN), which uses opportunistic network and wireless sensor network technologies to create a dynamic mesh network of potential victims, rescuers, and defibrillators. The LMN works by detecting a fatal arrhythmia with a wearable sensor device, localizing the victim and the nearest AED with nearby smartphones, and notifying VFRs through peer-to-peer communication. While there are challenges and limitations to implementing the LMN in society, this innovative network technology would reduce the tragedy of sudden cardiac death from OHCA.

Psychological impact of exceptional response in people with advanced cancer: a qualitative exploration.

BACKGROUND: In the cancer context, exceptional response incorporates unusual or unexpected response to anti-cancer treatment. For this study, exceptionally 'good' responses are defined as progression-free survival of more than three times the median from comparable trials. We aimed to explore how people meeting the definition of exceptional response to systemic cancer treatment experience adjust to their unexpected survivorship. METHODS: Individuals with 'exceptional response' to anti-cancer therapy nationally were referred by their treating clinicians to the Exceptional Responders Program. We conducted a qualitative sub-study involving semi-structured interviews with purposively selected participants. Those eligible had metastatic cancer, had survived at least 3 times the expected time since diagnosis, spoke English, and were aged > 18 years. Interviews were audiorecorded, transcribed and analysed thematically; and continued until thematic saturation was achieved. RESULTS: Twenty participants were interviewed. Thirteen were male (65%) with a median age of 63 years. Median time since cancer diagnosis was 6.5 years (range 3-18); survival times ranged between 3 and 10 times that expected. We identified four themes which varied in importance between individuals and over time. CONCLUSION: Exceptional responders may benefit from routine screening of distress and unmet needs to provide psychosocial support. Clinical services must focus on first capturing and then tailoring care to meet the diverse needs of this growing cohort. IMPLICATIONS FOR CANCER SURVIVORS: Adjustment to a diagnosis of advanced cancer and subsequent unexpected long-term survival is an often isolating experience and is common amongst exceptional responders. Seeking psychological and social support may assist with adjustment.

Dupilumab response onset, maintenance, and durability in patients with severe CRSwNP.

BACKGROUND: Responder analyses of SINUS phase 3 study data have shown clinically meaningful improvements across multiple chronic rhinosinusitis with nasal polyps (CRSwNP) outcomes with dupilumab. OBJECTIVE: To gain a better understanding of dupilumab response dynamics over 52 weeks. METHODS: Post hoc analysis using data from the SINUS-52 (NCT02898454) intention-to-treat population, of patients with severe CRSwNP who received dupilumab 300 mg once every 2 weeks (q2w) or placebo. Response, defined as an improvement from baseline of ≥ 1 point for Nasal Polyp Score (NPS), nasal congestion (NC), and loss of smell (LoS), and ≥ 8.9 points for 22-item Sino-Nasal Outcome Test (SNOT-22), was assessed for rapidity, maintenance, and durability. RESULTS: 303 patients (dupilumab, n = 150; placebo, n = 153) were included. For each outcome measure, a greater proportion of patients achieved first response by Week 16 (rapidity) with dupilumab vs placebo: NPS, 75.3% vs 39.2%; NC, 60.0% vs 24.2%; LoS, 60.7% vs 15.7%; and SNOT-22, 83.3% vs 66.0%. Among dupilumab patients with a response by Week 16, more than 80% maintained response at Week 52 (maintenance). Over 52 weeks, greater proportions of dupilumab patients were responders at ≥ 80% of time points: NPS, 46.7% vs 2.6%; NC, 46.7% vs 9.2%; LoS, 47.3% vs 3.9%; and SNOT-22, 62.0% vs 21.6% (durability). CONCLUSION: Most CRSwNP patients achieve clinically meaningful responses to dupilumab by Week 16, and most of these patients had maintenance and durability of response with continued treatment over time.

PeerOnCall: Exploring how organizational culture shapes implementation of a peer support app for public safety personnel.

BACKGROUND: Public safety personnel (PSP) such as firefighters, paramedics, and police are exposed to traumatic situations, which increase their risk for mental health issues. However, many PSP do not seek help in a timely manner. Peer support interventions have the potential to decrease stigma and increase treatment-seeking behaviours among PSP. However, little is known regarding how the organizational culture of public safety organizations (PSOs) affects the implementation of a peer-based intervention. This study aims to understand the extent to which organizational culture, including masculinity contest cultures (MCC), within Canadian PSOs could affect implementation of PeerOnCall, a new peer support app for PSP. METHODS: A qualitative multiple case study design was adopted, integrating semi-structured interviews with organizational champions from five PSOs. One to three champions from each PSO acted as key informants regarding their organizations. Interviews explored champions' perceptions of how organizational culture might shape implementation. Interview data were analyzed using inductive thematic analysis. RESULTS: Three themes were identified in analysis of the champion interviews. The first theme focused on external drivers and the second theme focused on internal drivers of organizational culture shift. The third theme focused on how culture can create resistance to implementation. Importantly, the MCC norm of show no weakness was described as a source of potential resistance when implementing the app. CONCLUSIONS: Each PSO had a unique and changing culture. Understanding how champions anticipate the role of culture in shaping implementation of an app-based intervention like PeerOnCall can guide the creation of contextually relevant strategies that optimize implementation within PSOs. Recommendations for optimizing implementation and areas for further study are provided.

Relationship between the response to donepezil and plasma amyloid beta oligomers in patients with Alzheimer's disease.

AIM: To date, there is no reported effective biomarker that can predict which Alzheimer's disease (AD) patients will respond to donepezil and which will not. This study aimed to investigate whether baseline values of Aß oligomers (AßOs), measured by the Multimer Detection System-Oligomeric Aß (MDS-OAß), can be used to predict responders after 6 months of donepezil medication. METHODS: The study enrolled 104 patients diagnosed with probable AD. After 6 months of donepezil medication, the response to treatment was evaluated by re-assessing the Korean version of the Mini-Mental State Examination (K-MMSE) and Clinical Dementia Rating scale-Sum of Box (CDR-SB) scales conducted at baseline. The patients were categorized into two groups according to the baseline MDS-OAß values known as the cut-off for AD diagnosis: a group with values below 0.78 and another group with values equal to or above 0.78. RESULTS: After 6 months of medication, the number of responders was 50 (49.5%). Responders exhibited significantly worse baseline CDR, CDR-SB, K-MMSE, and Barthel index compared with non-responders. There was a significantly higher number of responders among patients with MDS-OAß values below the cut-off of 0.78 compared with those with values equal to or above this threshold. Furthermore, there was a significant improvement in the K-MMSE and CDR-SB after 6 months of donepezil medication in patients with MDS-OAß values below 0.78 compared with those with values equal to or above 0.78. CONCLUSIONS: Baseline MDS-OAß values might constitute a novel biochemical marker for the efficacy of 6 months of donepezil treatment in AD. Geriatr Gerontol Int 2024; ••: ••-••.

A Scoping Review of Trauma, Mental Health and First Responders in Australia.

Exposure to traumatic and/or violent events is an inherent part of the first responder role, which increases the risk of developing acute and chronic mental health symptoms and conditions. Suicidality for Australian first responders have recently increased with prevalence considered much higher compared with the general population. To inform specific recommendations for Australian first responders, there is a need to establish what evidence is available regarding these issues within the Australian context. The aim of this scoping review was to explore the impacts of trauma on the mental health of Australian first responders, the strategies recommended to address these issues and any unique needs in rural contexts. A scoping review was undertaken following PRISMA guidelines for scoping reviews. Peer-reviewed articles on Australian first responder mental health from seven databases were screened for inclusion. This review highlights that despite available evidence on the types of traumas and adverse mental health outcomes experienced, less evidence exists pertaining to intervention effectiveness. There are major gaps in evidence within rural and remote contexts which hinders effective planning and delivery of support for rural and regional first responders. Clinicians such as mental health nurses, particularly in rural areas, need to be aware of these gaps which impact planning and delivery of support and are in prime position to ensure screening, interventions and strategies are used and evaluated to determine their suitability for rural first responders.

A Novel Liver Fibrosis Marker FIB-5 Index Predicted Response to Cardiac Resynchronization Therapy and Prognostic Outcomes in Patients With Heart Failure.

BACKGROUND: The fibrosis-5 (FIB-5) index is a noninvasive marker for assessing the progression of liver fibrosis and predictor in patients with heart failure (HF). This study investigated the association between the FIB-5 index and response to cardiac resynchronization therapy (CRT) and evaluated its predictive value for prognosis. METHODS: In total, 203 patients who underwent CRT/CRT-defibrillator (CRT-D) implantation were retrospectively included. The FIB-5 index was calculated using blood samples obtained before and after CRT/CRT-D. Response to CRT was defined as a relative reduction in left ventricular end-systolic volume of ≥15% 6 months after CRT/CRT-D. We compared the prognosis after CRT/CRT-D between the groups according to the FIB-5 index. RESULTS: One hundred and twenty-three patients (61%) responded to CRT. The responder group demonstrated a significantly higher FIB-5 index than the nonresponder group (-2.76 ± 3.85 vs. -4.67 ± 3.29, p < 0.001). Receiver-operating characteristic analysis demonstrated that the area under the curve of the FIB-5 index was 0.660 with a cutoff value of -4.00 for responders. In multivariate analysis, FIB-5 index ≥ -4.00 was an independent predictor for CRT response (odds ratio: 3.665, p = 0.003), in addition to QRS duration ≥ 150 ms and echocardiographic dysynchrony. The FIB-5 index increased significantly after 6 months in the responder group but not in the nonresponder group. The FIB-5 index ≥ -4.00 group showed a significantly better prognosis for cardiac death, HF hospitalization, and composite endpoint than the FIB-5 index < -4.00 group. CONCLUSION: The FIB-5 index in addition to classical predictors may be a useful marker for predicting response to CRT.

The gap between statistical and clinical significance: time to pay attention to clinical relevance in patient-reported outcome measures of insomnia.

BACKGROUND: Appropriately defining and using the minimal important change (MIC) and the minimal clinically important difference (MCID) are crucial for determining whether the results are clinically significant. The aim of this study is to survey the status of randomized controlled trials (RCTs) for insomnia interventions to assess the inclusion and interpretation of MIC/MCID values. METHODS: We conducted a cross-sectional study to survey the status of RCTs for insomnia interventions to assess the inclusion and appropriate interpretation of MIC/MCID values. A literature search was conducted by searching the main sleep medicine journals indexed in PubMed, the Excerpta Medica Database (EMBASE), and the Cochrane Central Register of Controlled Trials (CENTRAL) to identify a broad range of search terms. We included RCTs with no restriction on the intervention. The included studies used the Insomnia Severity Index (ISI) or the Pittsburgh Sleep Quality Index (PSQI) questionnaire as the outcome measures. RESULTS: 81 eligible studies were identified, and more than one-third of the included studies used MIC/MCID (n = 31, 38.3%). Among them, 21 studies with ISI as the outcome used MIC defined as a relative decrease ranging from 3 to 8 points. The most frequently used MIC value was a 6-point decrease (n = 7), followed by 8-point (n = 6) and 7-point decrease (n = 4), a 4 to 5-points decrease (n = 3), and a 30% reduction from baseline; 6 studies used MCID values, ranging from 2.8 to 4 points. The most frequently used MCID value was a 4-point decrease in the ISI (n = 4). 4 studies with PSQI as the outcome used a 3-point change as the MIC (n = 2) and a 2.5 to 2.7-point difference as MCID (n = 2). 4 non-inferiority design studies considered interval estimation when drawing clinically significant conclusions in their MCID usage. CONCLUSIONS: The lack of consistent MIC/MCID interpretation and usage in outcome measures for insomnia highlights the urgent need for further efforts to address this issue and improve reporting practices.

Budget impact and cost per responder analysis of upadacitinib for the treatment of moderate to severe atopic dermatitis from the perspective of the social security and the private sector in Argentina.

OBJECTIVES: Our study assessed the budget impact and cost per responder of upadacitinib15mg and 30 mg for moderate to severe atopic dermatitis (MS-AD) treatment fromsocial security and private health sector perspective in Argentina. METHODS: Abudget impact model was adapted to depict clinical and economic aspects oftreatment over a 5-years horizon time. Scenario analyses and deterministicsensitivity analyses were performed. A 16-weeks cost per responder model wasadapted based on a network meta-analysis. Primary analyses assessed the costper Eczema Area and Severity Index 50, 75 and 90 at week 16. RESULTS: The inclusion of upadacitinib 15 mg and 30 mg in the biological treatment mix forMS-AD was associated with an average budget saving per-member per-month ofU$S0.062 (social security) and U$S0.064 (private sector). Percentage ofpatients with access to treatment, acquisition cost of upadacitinib 30 mg andprevalence of MS-AD were the most influential parameters in the budget impactresults. At week 16, upadacitinib 30 mg was associated with the lowest numberneeded to treat and the lowest cost per responder for all outcomes. CONCLUSION: The introduction of upadacitinib in MS-AD treatment was associated with modestsavings for the social security and private payer budget in Argentina.

Pedagogical Implementation of Directive Feedback Manikins on Cardiopulmonary Resuscitation (CPR) Competencies: Expert Versus Peer Coaching.

BACKGROUND: Directive feedback manikins in resuscitation training evolved faster than the pedagogical evidence. Educators and learning systems must seek clarification on the efficacy of this technology to have evidence-based practices. This project explores directive feedback device use in cardiopulmonary resuscitation (CPR) education for laypersons. METHODS: A prospective nonrandomized-controlled design assessed two pedagogical approaches of directive feedback manikins in adult CPR lessons. The 230 participants were distributed between three groups: a control group without directive feedback manikins (no lights, NL), an expert coaching (EC) group with directive feedback and educator interpretation, and a peer coaching (PC) group with directive feedback, peer interpretation, and expert quality assurance. RESULTS: From the 25 courses observed, average compression depth (mm) did not differ between groups (p = .498), average compression rate (compressions: minute) significantly differed between groups (p = .004), and correct hand placement did not differ between groups (p = .249). A chi-square test showed no significant association between groups and CPR skill feedback, or between groups and "recommending the course to a friend or family member." The PC group was more likely to agree that they could "coach someone to do CPR skills" than the NL or EC. CONCLUSIONS: This study expands the knowledge base of directive feedback manikins in a pedagogical setting to improve CPR competencies. Training organizations may consider any of these practices effective, choosing those that align with desired outcomes. CPR educators need orientation to feedback devices as well as professional development on educational options for their use. Considerations for further research include technology costs, access, and cultural aspects of implementing these tools.

A prediction model for nonresponsive outcomes in critically ill patients with acute respiratory distress syndrome undergoing prone position ventilation: A retrospective cohort study.

OBJECTIVE: This study aimed to develop a reliable and effective nomogram model to identify high-risk populations with non-response to prone position ventilation (PPV) in acute respiratory distress syndrome (ARDS) patients. METHODS: This retrospective cohort study included 175 patients with ARDS undergoing PPV. An improvement of ≥ 20 mmHg in the PaO2/FiO2 after the first PPV was defined as a 'response'. For the construction of the model, all patients were randomly assigned to the train and validation cohort according to 2:1. Multivariate logistic regression was useed to develop the nomogram. The area under the receiver operating characteristic curve (AUC), decision curve and calibration curve were assessed to evaluate the efficiency, clinical utility and calibration of the model. RESULTS: The overall rate of non-response to PPV in ARDS patients was approximately 32.6 %. In the training cohort and validation cohort, the rate are 29.9 % and 34.5 % respectively. Murray score ≥ 2.5 (OR: 4.29), procalcitonin (PCT) ≥ 2 ng/mL (OR: 2.52), N-terminal pro-B-type natriuretic peptide (Nt-proBNP) ≥ 2000 pg/ml (OR: 2.44), and hemoglobin ≤ 90 g/L (OR: 2.39) were independently associated with the rate of non-response to PPV and combined in prediction model. The model demonstrated good predictive value with AUC of 0.817 and 0.828 in the train and validation cohort. Calibration curve showed good calibration and decision curve analysis indicated favorable clinical utility. CONCLUSIONS: This study constructed a risk prediction model for non-response to PPV, which demonstrated good predictive value and clinical utility. IMPLICATIONS FOR CLINICAL PRACTICE: Early identification of prone position response in ARDS is essential for timely alternative treatments, improving patient prognosis and healthcare efficiency. The predictive model included representative indicators of patients with ARDS, encompassing parameters such as the acute lung injury (Murray score), cardiac function (Nt-proBNP), infectious status (PCT), and hemoglobin levels.

Exploring Responsiveness to Highly Challenging Balance and Gait Training in Parkinson's Disease.

BACKGROUND: Exercise potentially improves gait, balance, and habitual physical activity in Parkinson's disease (PD). However, given the heterogeneous nature of the disease, it is likely that people respond differently to exercise interventions. Factors determining responsiveness to exercise interventions remain unclear. OBJECTIVES: To address this uncertainty, we explored the responsiveness to our highly challenging balance and gait intervention (HiBalance) in people with PD. METHODS: Thirty-nine participants with mild-moderate PD who underwent the HiBalance intervention from our randomized controlled trial were included. We defined response in three domains: (1) balance based on Mini-BESTest, (2) gait based on gait velocity, and (3) physical activity based on accelerometry-derived steps per day. In each domain, we explored three responsiveness levels: high, low, or non-responders according to the change from pre- to post-intervention. Separate Random Forests for each responder domain classified these responsiveness levels and identified variable importance. RESULTS: Only the Random Forest for the balance domain classified all responsiveness levels above the chance level indicated by a Cohen's kappa of "slight" agreement. Variable importance differed among the responsiveness levels. Slow gait velocity indicated high responders in the balance domain but showed low probabilities for low and non-responders. For low and non-responders, fall history or no falls, respectively, were more important. CONCLUSIONS: Among three responder domains and responsiveness levels, we could moderately classify responders in the balance domain, but not for the gait or physical activity domain. This can guide inclusion criteria for balance-targeted, personalized intervention studies in people with PD.

Omalizumab in Chronic Spontaneous Urticaria: A Real-World Study on Effectiveness, Safety and Predictors of Treatment Outcome.

Background: Although omalizumab has shown success in treating chronic spontaneous urticaria (CSU) patients unresponsive to antihistamines, the exact mechanism of action and predictive markers of response remain unclear. Purpose: The aim of this study was to examine the correlation between baseline levels of biomarkers and clinical parameters with omalizumab response and response rate in patients with CSU. Methods: This retrospective study included 82 adult CSU patients who received omalizumab 300mg every 4 weeks for 16 weeks between January 2022 and December 2023. Treatment response was assessed using UAS7 and DLQI scores at baseline and weeks 4, 8, 12, and 16. Responders were defined as patients achieving UAS7 < 7, with early and late responders categorized based on response within or after 4 weeks, respectively. Baseline clinical features and laboratory biomarkers were compared between responders and non-responders. Results: The overall response rate was 71.95% (59/82), with 23 early responders and 36 late responders. Responders had significantly lower baseline UAS7 (median: 28 vs 35, P < 0.01), DLQI (median: 8 vs 15, P < 0.001), and IL-17 levels (median: 0.53 vs 1.26 pg/mL, P < 0.001) compared to non-responders. Baseline UAS7 > 31, DLQI > 9.5, and IL-17 > 0.775 pg/mL predicted non-response with sensitivities of 78.26%, 100%, and 78.26%, and specificities of 67.8%, 59.32%, and 72.88%, respectively. ASST positivity and comorbid allergic diseases were associated with early response (P < 0.05). Adverse events were reported in 6.09% of patients, including mild injection site reactions and transient urticaria exacerbation, not requiring treatment discontinuation. Conclusion: This study suggests that omalizumab is an effective and safe treatment option for antihistamine-refractory CSU. Baseline UAS7, DLQI, ASST status, serum total IgE levels, and IL-17 may serve as potential predictors of omalizumab response. Notably, ASST positivity and comorbid allergic diseases were associated with an early response to treatment. These findings highlight the importance of considering individual patient characteristics when predicting the likelihood and timing of response to omalizumab in CSU.

Characterization of early non-responders within behavioral weight loss treatment.

Objective: Given that low early (4 weeks) weight loss (WL) predicts longer-term WL, the purpose of this study was to identify factors associated with poor early WL. Methods: 438 adults with overweight/obesity participating in an Internet-delivered behavioral WL program provided weights at baseline and 4 weeks. Participants were stratified by percent WL at 4 weeks: LOW: <2% WL, MEDIUM: 2 to <4% WL, HIGH: ≥4% WL and groups were compared on baseline variables (demographics, physical activity, and psychosocial measures) and 4-week intervention adherence. Results: 37.4%, 40.9%, and 21.7% of participants had LOW, MEDIUM, and HIGH early WL respectively. LOW was more likely to be female compared to HIGH and less likely to be non-Hispanic White compared to MEDIUM and HIGH (p's<0.05). After controlling for demographic differences, LOW had lower baseline physical activity compared to HIGH and watched fewer video lessons, self-monitored calorie intake and weight on fewer days, and were less likely to achieve the exercise goal compared to MEDIUM and HIGH (p's<0.05). Conclusion: Findings can inform future adaptive interventions which tailor treatment based upon early WL to improve WL outcomes for more individuals.

Increasing cost-effectiveness of AEDs using algorithms to optimise location.

OBJECTIVES: Volunteer responder systems (VRSs) aim to decrease time to defibrillation by dispatching trained volunteers to automated external defibrillators (AEDs) and out-of-hospital cardiac arrest (OHCA) victims. AEDs are often underutilized due to poor placement. This study provides a cost-effectiveness analysis of adding AEDs at strategic locations to maximize quality-adjusted life years (QALYs). METHODS: We simulated combined volunteer, police, firefighter, and emergency medical service response scenarios to OHCAs, and applied our methods to a case study of Amsterdam, the Netherlands. We compared the competing strategies of placing additional AEDs, using steps of 40 extra AEDs (0, 40, …, 1480), in addition to the existing 369 AEDs. Incremental cost-effectiveness ratios (ICERs) were calculated for each increase in additional AEDs, from a societal perspective. The effect of AED connection and time to connection on survival to hospital admission and neurological outcome at discharge was estimated using logistic regression, using OHCA data from Amsterdam from 2006 to 2018. Other model inputs were obtained from literature. RESULTS: Purchasing up to 1120 additional AEDs (ICER €75,669/QALY) was cost-effective at a willingness-to-pay threshold of €80,000/QALY, when positioned strategically. Compared to current practice, adding 1120 AEDs resulted in a gain of 0.111 QALYs (95% CI 0.110-0.112) at an increased cost of €3792 per OHCA (95% CI €3778-€3807). Health benefits per AED diminished as more AEDs were added. CONCLUSIONS: Our study identified cost-effective strategies to position AEDs at strategic locations in a VRS. The case study findings advocate for a substantial increase in the number of AEDs in Amsterdam.

The Impact of Smoking on Long-Term Protection Following Hepatitis B Vaccination: A 24-Year Cohort Study.

The hepatitis B vaccination-induced immune response has been demonstrated to be associated with a number of factors, including age, sex, BMI, and the presence of comorbidities. Additionally, modifiable determinants such as smoking have been identified as influencing the response to vaccination. However, despite the evidence that smokers are at an increased risk of not responding to vaccination, the long-term effects of smoking on antibody persistence remain poorly understood. This study aims to assess the impact of smoking habits on long-term immunity following the primary vaccination cycle. Participants were required to have received a standard three-dose vaccine schedule in childhood, without subsequent doses, and to be between 18 and 24 years of age. Data on age, sex, BMI, age of administration of the first vaccine dose, and time between doses were collected. An antibody concentration < 10 IU/L was considered as non-protective. A total of 2133 individuals were included, 14.2% of whom were smokers. The mean age was 20.28 ± 0.92 years. The probability of having a non-protective antibody concentration was significantly higher in smokers than in non-smokers (AOR: 1.287; 95% CI: 1.002-1.652). The detrimental effects of smoking extend beyond the immediate effects on the vaccine response, also impairing the long-term immune response in individuals who received vaccinations during childhood.

Progression-Free Survival and Treatment-Free Interval in Head and Neck Cancer with Long-Term Response to Nivolumab: Timing of Active Discontinuation.

The optimal timing for actively discontinuing immune checkpoint inhibitor therapy in long-term responders with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) remains unresolved. We conducted a retrospective study of 246 patients with R/M HNSCC treated with nivolumab to determine the optimal timing to actively discontinue nivolumab therapy. We examined the point at which progression-free survival (PFS) plateaued in all cases. We compared the prognosis of 19 (7.7%) ongoing cases and 227 (92.3%) discontinued cases and analyzed treatment duration and treatment-free interval (TFI). The 6-year overall survival was 11.8% (median, 12.1), and the 6-year PFS was 15.3% (median, 3.0). The PFS curve remained stable for 3 years. The median duration of nivolumab treatment was 2.9 months (range 0.03-81.9): Ongoing group, 41.8 (5.6-81.9); Decision group, 36.8 (4.0-70.1); Toxicity group, 30.6 (2.8-64.8); and progressive disease group, 2.0 (0.03-42.9). TFI in the Decision group was 15.1 months (0.6-61.6) and 30.6 months (2.8-64.8) in the Toxicity group. Long-term responses in R/M HNSCC patients treated with nivolumab are rare but gradually increasing. For this patient group, our best estimate of the optimal time to end treatment is 3 years, as the PFS in this study reached a plateau at that timepoint.

Network approach reveals preferential T-cell and macrophage association with α-linked ß-cells in early stage of insulitis in NOD mice.

One of the challenges in studying islet inflammation-insulitis-is that it is a transient phenomenon. Traditional reporting of the insulitis progression is based on cumulative, donor-averaged values of leucocyte density in the vicinity of pancreatic islets, that hinder intra- and inter-islet heterogeneity of disease progression. Here, we aimed to understand why insulitis is non-uniform, often with peri-insulitis lesions formed on one side of an islet. To achieve this, we demonstrated the applicability of network theory in detangling intra-islet multi-cellular interactions during insulitis. Specifically, we asked the question "What is unique about regions of the islet that interact with immune cells first". This study utilized the non-obese diabetic mouse model of type one diabetes and examined the interplay among α-, ß-, T-cells, myeloid cells, and macrophages in pancreatic islets during the progression of insulitis. Disease evolution was tracked based on the T/ß cell ratio in individual islets. In the early stage, we found that immune cells are preferentially interacting with α-cell-rich regions of an islet. At the islet periphery α-linked ß-cells were found to be targeted significantly more compared to those without α-cell neighbors. Additionally, network analysis revealed increased T-myeloid, and T-macrophage interactions with all ß-cells.

RAndomized Cluster Evaluation of Cardiac ARrest Systems (RACE-CARS) trial: Study Rationale and Design.

Out-of-hospital cardiac arrest (OHCA) occurs in nearly 350,000 people each year in the United States (US). Despite advances in pre- and in-hospital care, OHCA survival remains low and is highly variable across systems and regions. The critical barrier to improving cardiac arrest outcomes is not a lack of knowledge about effective interventions, but rather the widespread lack of systems of care to deliver interventions known to be successful. The RAndomized Cluster Evaluation of Cardiac ARrest Systems (RACE-CARS) trial is a 7-year pragmatic, cluster-randomized trial of 60 counties (57 clusters) in North Carolina using an established registry and is testing whether implementation of a customized set of strategically targeted community-based interventions improves survival to hospital discharge with good neurologic function in OHCA relative to control/standard care. The multi-faceted intervention comprises rapid cardiac arrest recognition and systematic bystander CPR instructions by 9-1-1 telecommunicators, comprehensive community CPR training and enhanced early automated external defibrillator (AED) use prior to emergency medical systems (EMS) arrival. Approximately 20,000 patients are expected to be enrolled in the RACE CARS Trial over 4 years of the assessment period. The primary endpoint is survival to hospital discharge with good neurologic outcome defined as a cerebral performance category (CPC) of 1 or 2. Secondary outcomes include the rate of bystander CPR, defibrillation prior to arrival of EMS, and quality of life. We aim to identify successful community- and systems-based strategies to improve outcomes of OHCA using a cluster randomized-controlled trial design that aims to provide a high level of evidence for future application.