Timeliness of reperfusion in ST-segment elevation myocardial infarction and outcomes in Kerala, India: results of the TRUST outcomes registry.

PURPOSE: Transatlantic guidelines endorse quality metrics for timely reperfusion in patients with ST-elevation myocardial infarction (STEMI). Compliance in low- and middle-income countries (LMICs) is largely unknown. STUDY DESIGN: We prospectively evaluated 2928 STEMI patients in Kerala, India, across 16 PCI-capable hospitals who received reperfusion with either primary percutaneous coronary intervention (PPCI) or fibrinolysis. Primary endpoint was a major adverse cardiovascular event (MACE) composite of death, non-fatal myocardial infarction, stroke or readmission for heart failure at 1-year. RESULTS: Among reperfused STEMI patients, 320 (10.9%) received timely reperfusion with either PPCI or fibrinolysis, 1985 (67.8%) received delayed PPCI, and 623 (21.3%) received delayed fibrinolysis. Timely reperfusion had lower unadjusted MACE rates than delayed PCI or fibrinolysis (timely reperfusion: 11.9%, delayed PPCI: 13.6%, delayed fibrinolysis: 23.9%, P < 0.001). Mortality was lowest in the timely reperfusion group (timely reperfusion: 6.3%, delayed PPCI: 7.8%, delayed fibrinolysis 18.8%, P < 0.001). After multivariate analysis, delayed fibrinolysis had a higher MACE rate (HR 1.52 95% CI 1.04-2.21) and mortality (HR 1.97, 95% CI 1.18-3.25) compared to timely reperfusion. Total ischemic time > 3 h and delayed first medical contact-to-needle time predicted MACE at 1 year. CONCLUSIONS: Among STEMI patients in Kerala, India, only one in 10 eligible patients received timely reperfusion. Longer total ischemic times and delayed fibrinolysis were associated with 1-year MACE. Improving timely reperfusion is critical to enhancing STEMI outcomes in LMICs. What is already known on this topic Given the established link between delay to reperfusion and worse major adverse cardiac events (MACE), global efforts have concentrated on minimizing different components of the total ischemic time to improve ST-elevation myocardial infarction (STEMI) outcomes. Compliance in low- and middle-income countries (LMICs) is largely unknown. What this study adds In this cohort of STEMI patients in Kerala, India, total ischemic time and first medical contact-to-needle time correlated with long-term MACE rates, whereas other timeliness indicators did not. How this study might affect research, practice or policy Our study highlights the significant barriers to accessing STEMI care that are prevalent in LMICs despite incremental growth in the number of PCI-capable hospitals. The pre-hospital phase within total ischemic time is the most important quality improvement metric of STEMI care in LMICs, especially for patients chosen for fibrinolysis.

Long-Term Survival Outcomes With First-Line Nivolumab Plus Ipilimumab-Based Treatment in Patients With Metastatic Non-Small Cell Lung Cancer and Tumor PD-L1 <1%: a Pooled Analysis.

INTRODUCTION: Nivolumab plus ipilimumab-based treatment regimens have shown long-term, durable efficacy benefit in patients with metastatic non-small cell lung cancer (NSCLC). Here we report clinical outcomes from a pooled analysis of patients with metastatic NSCLC and tumor programmed death ligand 1 (PD-L1) <1% treated with first-line nivolumab plus ipilimumab with or without two cycles of chemotherapy versus up to four cycles of chemotherapy in the randomized phase 3 CheckMate 227 and CheckMate 9LA studies. METHODS: Patients were aged ≥18 years and had stage IV/recurrent NSCLC with no sensitizing EGFR/ALK alterations. Assessments included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), and safety. RESULTS: In patients with tumor PD-L1 <1% in the nivolumab plus ipilimumab with or without chemotherapy (n = 322) versus chemotherapy (n = 315) arms, median OS was 17.4 versus 11.3 months, respectively, (hazard ratio [HR] = 0.64; 95% confidence interval [CI]: 0.54-0.76; 5-year OS rate, 20% versus 7%) at a median follow-up of 73.7 months. OS benefit was observed across key subgroups, including difficult-to-treat populations such as those with baseline brain metastases (HR = 0.44; 95% CI: 0.26-0.75) or squamous NSCLC (HR = 0.51; 95% CI: 0.36-0.72). In the overall pooled population, median PFS was 5.4 versus 4.9 months (HR = 0.72; 95% CI: 0.60-0.87; 5-year PFS rate, 9% versus 2%), ORR was 29% versus 22%, and median DOR was 18.0 versus 4.6 months. No new safety signals were observed. CONCLUSION: Nivolumab plus ipilimumab with or without chemotherapy provides a long-term, durable clinical benefit in patients with metastatic NSCLC and tumor PD-L1 <1%, supporting the use of this strategy as a first-line treatment option in this population with high unmet need.

Intracardiac vs. transesophageal echocardiography guided transcatheter closure of patent foramen ovale and atrial septal defects.

Transcatheter closure of atrial septal defects (ASD) and patent foramen ovale (PFO) can be performed with transesophageal echocardiography (TEE) or intracardiac echocardiography (ICE) guidance, but data comparing both modalities in contemporary practice is lacking. Using ICD-10 codes, patients who underwent transcatheter ASD/PFO closure between 2016 and 2020 using ICE or TEE in the Nationwide Readmissions Database (NRD) were identified. Propensity-score matching was performed to compare in-hospital adverse events, length of stay (LOS), cost, and 30-day non-elective readmissions. A total of 964 patients underwent ASD/PFO closure with ICE (38.3 %, n = 369) or TEE (61.7 %, n = 595) between 2016 and 2020. Propensity score matching yielded 327 patients in each group, which were well balanced. Median (IQR) age was 59.0 (46.0, 72.0) years and 54.7 % were female. No difference was observed in the rate of in-hospital major adverse events between groups. ICE guidance was associated with a lower median cost (ICE $20,140.1 (14,622.3, 25,027.0) vs TEE $20,740.4 (14,137.5, 33,045.3), p < 0.04). In conclusion, ICE guided ASD/PFO closure was associated with lower hospitalization cost without increasing in-hospital adverse events when compared with TEE guidance.

Choroidal thickness after anti-VEGF in typical neovascular age-related macular degeneration - A systematic review and meta-analysis.

Age-related macular degeneration (AMD) is one of the leading causes of blindness in the world and anti-vascular endothelial growth factor (VEGF) injections have been the standard of care for the wet/neovascular variant since 2004. Currently, there are conflicting reports regarding its effect on the choroid, which supplies outer retina with oxygen and other nutrients. We synthesize available information of anti-VEGF on choroidal thickness (CT) in treatment-naïve typical neovascular AMD patients during the initial 12-week loading phase. We found 43 studies involving 1901 eyes from 1878 patients were included. Meta-analysis of 35 studies reporting CT at baseline and after 12 weeks suggested a significant decrease in CT with anti-VEGF treatment. A greater mean change with aflibercept compared to ranibizumab was found in subgroup analyses of sub-foveal CT in types 1 and 2 macular neovascularization. The long-term consequences of reduced CT in neovascular AMD remain unclear and require further targeted studies.

Five-year outcomes with first-line nivolumab plus ipilimumab with 2 cycles of chemotherapy versus 4 cycles of chemotherapy alone in patients with metastatic non-small cell lung cancer in the randomized CheckMate 9LA trial.

BACKGROUND: We report 5-year efficacy and safety outcomes from CheckMate 9LA in patients with metastatic non-small cell lung cancer (mNSCLC) and exploratory analyses in key patient subgroups. METHODS: Adults with stage IV/recurrent NSCLC and no sensitizing EGFR/ALK alterations were randomized to receive nivolumab plus ipilimumab with chemotherapy (n = 361) or chemotherapy (n = 358). Outcomes were assessed in all randomized patients and subgroups. RESULTS: With 57.3 months' minimum follow-up, patients continued to derive overall survival (OS) benefit with nivolumab plus ipilimumab with chemotherapy over chemotherapy (HR, 0.73; 95% CI, 0.62-0.85; 5-year OS rates, 18% vs. 11%), regardless of tumor programmed death ligand 1 (PD-L1) expression (PD-L1 < 1%, 22% vs. 8%; PD-L1 ≥ 1%, 18% vs. 11%), histology (squamous, 18% vs. 7%; non-squamous, 19% vs. 12%), or presence of baseline brain metastases (20% vs. 6%). Five-year duration of response (DOR) rates were 19% versus 8% with nivolumab plus ipilimumab with chemotherapy versus chemotherapy, with consistent benefit across subgroups. Patients who discontinued nivolumab plus ipilimumab with chemotherapy due to treatment-related adverse events had a 5-year OS rate of 37%. Five-year progression-free survival and DOR rates in 5-year survivors were 55% versus 38% and 59% versus 46%, respectively. No new safety signals were observed in 5-year survivors, regardless of the number of ipilimumab doses received. CONCLUSION: This 5-year update supports the long-term, durable OS benefit and improved 5-year survivorship with nivolumab plus ipilimumab with chemotherapy over chemotherapy in patients with mNSCLC, regardless of tumor PD-L1 expression or histology. GOV REGISTRATION: NCT03215706.

ALKTERNATE: A Pilot Study Alternating Lorlatinib With Crizotinib in ALK-Positive NSCLC With Prior ALK Inhibitor Resistance.

Introduction: ALK-positive lung cancers represent a molecularly diverse disease. With drug exposure, driving selection pressure, and resistance pathways, disease relapse will emerge. There is compelling rationale to investigate novel treatment strategies, informed by dynamic circulating tumor DNA (ctDNA) monitoring. Methods: The single-arm, pilot study ALKTERNATE investigated fixed alternating cycles of lorlatinib intercalated with crizotinib in individuals resistant to second-generation ALK inhibitors. Dynamic ctDNA explored the correlation with disease response and disease recurrence and defined disease resistance. The primary outcome was time-to-treatment failure, a composite of tolerability, feasibility, and efficacy. Secondary outcomes included standard survival measures, toxicity, pharmacokinetic analysis, and patient-reported outcomes. Tertiary outcomes were proteogenomic analyses of tissue and plasma. Results: A total of 15 individuals were enrolled; three encountered primary resistance to lorlatinib induction. There were 12 participants who received alternating therapy, and this approach revealed safety, feasibility, and effectiveness. Patient-reported outcomes were maintained or improved on therapy, and toxicity was consistent with previous reports. The pharmacokinetic measures were similar to the single-arm drug experience. Median time-to-treatment failure was 10 months; overall survival was 23 months. ctDNA profiles indicated inferior survival in those with preexistent TP53 mutations and those without clear or cleared ctDNA at trial induction. The study defined a vastly heterogeneous population with an abundance of ALK coexisting with non-ALK resistance variants. Conclusions: ALKTERNATE revealed feasibility with a novel alternating ALK inhibitor strategy in ALK-positive NSCLC. Results support progressing inquiry into this approach and propose a flexible design with drug(s) selected and alternating time frames, informed by real-time plasma profiling. Moving this concept to treatment naive may also optimize impact.

Evaluation of the Implementation of a Novel Fluid Resuscitation Device in the Prehospital Care of Sepsis Patients: Application of the Implementation Outcomes Framework.

OBJECTIVES: Early identification and fluid resuscitation are recognized performance measures within sepsis care. Despite fluid resuscitation, fluid goals are often not achieved in the prehospital environment. Furthermore, description of implementation process and evaluation of implementation success are historically underreported in prehospital research. The objective of this study was to contextualize and evaluate the system-wide implementation of a novel fluid resuscitation device, the LifeFlow PLUS®, in the treatment of prehospital sepsis patients. METHODS: A single urban emergency medical services (EMS) system internally decided to adopt a novel fluid resuscitation device. This EMS system added the device to the clinical care guidelines of suspected sepsis patients. Prior to and during implementation of the new guidelines, several strategies were undertaken to promote consistent, appropriate system-wide use of the device. A mixed methods study design was deployed. Surveys of EMS clinicians and leaders assessed perceptions of the device and sepsis education prior to field implementation of the device. Clinician and leader semi-structured interviews assessed implementation experience and device adoption. Document analysis evaluated deployment of implementation strategies. Data were triangulated to contextualize implementation and evaluate success. RESULTS: Clinician (88%) and leader (91%) confidence in appropriate clinician device use and device superiority for sepsis care (73 and 100%, respectively) were high. Clinicians (58%) were less likely to view the device as easy to implement compared to leaders (73%). Three themes were developed from semi-structured interviews, including "exposure" to the device, "reinforcing factors" to prompt device use, and "clinician buy-in." Twenty unique implementation strategies (e.g., dynamic trainings, mandating change) were used to promote successful system-wide device adoption. CONCLUSIONS: The overall implementation success of this novel fluid resuscitation device was moderate. Barriers to adoption included complexity of clinical decision-making and ease of device use. Facilitators to adoption included the use of multiple modes of education, clinical reminders, presenting evidence of device benefit, and prehospital culture. Prior to future prehospital implementation programs, EMS systems should focus on identifying and addressing key barriers and facilitators to improve adoption.

Cefazolin-induced hemolytic anemia in septic arthritis: A case report.

A 50-year-old woman living with untreated HIV and injection drug use presented with right shoulder pain. The shoulder exam and computed tomography (CT) scan were concerning for septic arthritis. She was started on empiric vancomycin and cefepime and underwent right shoulder debridement and humeral head resection. Bone cultures grew methicillin sensitive Staphylococcus aureus (MSSA); empiric broad-spectrum antibiotics were changed to cefazolin. The patient subsequently developed severe anemia refractory to blood transfusions approximately 6 days later. Further evaluation disclosed hemolytic anemia attributable to cefazolin. Antibiotic therapy was switched from cefazolin to daptomycin, and the patient was started on prednisone. She had sustained improvement in hemoglobin values above 6 g/dL without requiring further transfusions prior to hospital discharge. Drug-induced immune hemolytic anemia from cefazolin is rare but has been reported primarily in the perioperative setting. Here, we present a case following initiation of treatment for septic arthritis.

Non-cosmetic use of botulinum toxin in surgical conditions.

Botulinum toxin (BTX) is a neurotoxin that has an ability to create a fully reversible relaxation of muscles through decreased release of acethylcholin. It also has an effect on the cholinergic autoimmune nervous system, and it can reduce pain sensitization. BTX is widely used in cosmetic treatments. In recent years, BTX has increasingly been used to treat several medical and surgical conditions. In many cases, this is despite weak evidence and without approval from the European Medicine Agency (EMA). This narrative review describes how BTX is used in the different surgical specialties and provides a brief overview of the use of BTX for non-cosmetic surgical conditions.

Utilizing nerve conduction studies to identify very early Guillain-Barré syndrome and distinguish it from mimics in emergency settings.

INTRODUCTION/AIMS: Accurately diagnosing Guillain-Barré syndrome (GBS) in its early stages and distinguishing it from mimics poses challenges. This study aimed to evaluate the utility of an existing electrodiagnostic criterion in very early GBS (VEGBS) for discerning mimics. Additionally, we explored specific electrophysiological abnormalities in VEGBS to design a new diagnostic criterion for more accurate VEGBS diagnosis. METHODS: We retrospectively identified all patients with flaccid quadriparesis initially suspected of GBS who underwent nerve conduction studies (NCS) ≤4 days from symptom onset. We then retrieved their NCS data and applied an existing electrodiagnostic criterion for sensitivity and specificity analyses based on the final discharge diagnosis. Furthermore, we designed a new criterion based on the observed electrophysiological abnormalities that have maximum specificity and at least 50% sensitivity. RESULTS: Among 70 patients suspected of VEGBS, 44 (63%) received a final diagnosis of GBS, while in 26 (37%), the GBS diagnosis was later refuted. Umapathi's definite criterion exhibited a sensitivity of 61.36% and a specificity of 92.31%. The probable and possible groups showed very high sensitivity (90.91% and 100%, respectively); however, specificity was low (57.69% and 30.77%, respectively) in the very early stage. Our proposed criterion demonstrated a sensitivity of 88.64% (CI: 75.44%-96.21%) and a specificity of 96.15% (CI: 80.36%-99.90%). DISCUSSION: The criterion based on presumed electrophysiological correlates of specific early GBS pathophysiology proved more effective than the existing electrodiagnostic criterion in differentiating VEGBS from mimics.

Subcutaneous Versus Intravenous Amivantamab, Both in Combination With Lazertinib, in Refractory Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer: Primary Results From the Phase III PALOMA-3 Study.

PURPOSE: Phase III studies of intravenous amivantamab demonstrated efficacy across epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). A subcutaneous formulation could improve tolerability and reduce administration time while maintaining efficacy. PATIENTS AND METHODS: Patients with EGFR-mutated advanced NSCLC who progressed after osimertinib and platinum-based chemotherapy were randomly assigned 1:1 to receive subcutaneous or intravenous amivantamab, both combined with lazertinib. Coprimary pharmacokinetic noninferiority end points were trough concentrations (Ctrough; on cycle-2-day-1 or cycle-4-day-1) and cycle-2 area under the curve (AUCD1-D15). Key secondary end points were objective response rate (ORR) and progression-free survival (PFS). Overall survival (OS) was a predefined exploratory end point. RESULTS: Overall, 418 patients underwent random assignment (subcutaneous group, n = 206; intravenous group, n = 212). Geometric mean ratios of Ctrough for subcutaneous to intravenous amivantamab were 1.15 (90% CI, 1.04 to 1.26) at cycle-2-day-1 and 1.42 (90% CI, 1.27 to 1.61) at cycle-4-day-1; the cycle-2 AUCD1-D15 was 1.03 (90% CI, 0.98 to 1.09). ORR was 30% in the subcutaneous and 33% in the intravenous group; median PFS was 6.1 and 4.3 months, respectively. OS was significantly longer in the subcutaneous versus intravenous group (hazard ratio for death, 0.62; 95% CI, 0.42 to 0.92; nominal P = .02). Fewer patients in the subcutaneous group experienced infusion-related reactions (IRRs; 13% v 66%) and venous thromboembolism (9% v 14%) versus the intravenous group. Median administration time for the first infusion was reduced to 4.8 minutes (range, 0-18) for subcutaneous amivantamab and to 5 hours (range, 0.2-9.9) for intravenous amivantamab. During cycle-1-day-1, 85% and 52% of patients in the subcutaneous and intravenous groups, respectively, considered treatment convenient; the end-of-treatment rates were 85% and 35%, respectively. CONCLUSION: Subcutaneous amivantamab-lazertinib demonstrated noninferiority to intravenous amivantamab-lazertinib, offering a consistent safety profile with reduced IRRs, increased convenience, and prolonged survival.

Novel Hemodynamic, Vascular Lesion, and Cytokine/Chemokine Differences Regarding Sex in a Pulmonary Arterial Hypertension Model.

Sex differences are recognized in pulmonary hypertension. However, the progression of disease with regard to vascular lesion formation and circulating cytokines/chemokines is unknown. To determine whether vascular lesion formation, changes in hemodynamics, and alterations in circulating chemokines/cytokines differ between males and females, we used a progressive model of pulmonary arterial hypertension (PAH), Sugen/hypoxia, and analyzed cohorts of male and female rats at time points suggested to indicate worsening disease. Our analysis included echocardiography for hemodynamics, morphometry, immunofluoresecence, and chemokine/cytokine analysis of plasma at each time point in both sexes. We found that male rats had significantly increased Fulton index, compared with those for females at each time point, as well as increased medial artery thickening at 8 weeks of PAH. Furthermore, females exhibited fewer obliterative vascular lesions than males at our latest time point. Our data also show increased IL-4, granulocyte-macrophage colony-stimulating factor, IL-10, and macrophage interacting protein-1α that were not observed in females, whereas females were observed to have increased RANTES (whose name derives from Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted) and CXCL-10 that were not found in males. Males also have increased infiltrating macrophages in vascular lesions, compared with females. We found that development of progressive PAH in hemodynamics, morphology, and chemokine/cytokine circulation differs significantly between males and females. These data suggest a macrophage-driven pathology in males, whereas there may be T cell protection from vascular damage in females with PAH.

Repeatability of image quality in very low-field MRI.

BACKGROUND: Very low-field MR has emerged as a promising complementary device to high-field MRI scanners, offering several advantages. One of the key benefits is that very low-field scanners are generally more portable and affordable to purchase and maintain, making them an attractive option for medical facilities looking to reduce costs. Very low-field MRI systems also have lower RF power deposition, making them safer and less likely to cause tissue heating or other safety concerns. They are also simpler to maintain, as they do not require cooling agents such as liquid helium. However, these portable MR scanners are impacted by temperature, lower magnetic field strength, and inhomogeneity, resulting in images with lower signal-to-noise ratio (SNR) and higher geometric distortions. It is essential to investigate and tabulate the variations in these parameters to establish bounds so that subsequent in vivo studies and deployment of these portable systems can be well informed. PURPOSE: The aim of this work is to investigate the repeatability of image quality metrics such as SNR and geometrical distortion at 0.05 T over 10 days and three sessions per day. METHODS: We acquired repeatability data over 10 days with three sessions per day. The measurements included temperature, humidity, transmit frequency, off-resonance maps, and 3D turbo spin echo (TSE) images of an in vitro phantom. This resulted in a protocol with 11 sequences. We also acquired a 3 T data set for reference. The image quality metrics included computing SNR and eccentricity (to assess geometrical distortion) to investigate the repeatability of 0.05 T image quality. The image reconstruction included drift correction, k-space filtering, and off-resonance correction. We computed the experimental parameters' coefficient of variation (CV) and the resulting image quality metrics to assess repeatability. We have explored the impact of electromagnetic interference (EMI) on image quality in very low-field MRI. The investigation involved varying both the distance and amplitude of the EMI-producing coil from the signal generator to analyze their effects on image quality. RESULTS: The range of temperature measured during the study was within 1.5 °C. The off-resonance maps acquired before and after the 3D TSE showed similar hotspots and were changed mainly by a global constant. The SNR measurements were highly repeatable across sessions and over the 10 days, quantified by a CV of 6.7%. The magnetic field inhomogeneity effects quantified by eccentricity showed a CV of 13.7%, but less than 5.1% in two of the three sessions over 10 days. The use of conjugate phase reconstruction mitigated geometrical distortion artifacts. Temperature and humidity did not significantly affect SNR or mean frequency drift within the ranges of these environmental factors investigated. The EMI experiment showed that as the amplitude increased the SNR decreased, and concurrently the root mean square of the background increased with a rise in EMI amplitude or a reduction in distance. CONCLUSIONS: We found that humidity and temperature in the range investigated did not impact SNR or frequency. Based on the CV values computed session-wise and for the overall study, our findings indicate high repeatability for SNR and magnetic field homogeneity.

The "Personalising Actinic Keratosis Treatment for Immunocompromised Patients" (IM-PAKT) Project: An Expert Panel Opinion.

Actinic keratosis (AK) is an intraepithelial condition characterized by the development of scaly, erythematous lesions after repeated exposure to ultraviolet radiation. Significant immunosuppression is a risk factor for the development of AK and subsequent lesion progression to squamous cell carcinoma. Immunocompromised patients (ICPs), particularly organ transplant recipients, often have more advanced or complex AK presentations and an increased risk of skin carcinomas versus non-ICPs with AK, making lesions more difficult to treat and resulting in worse treatment outcomes. The recent "Personalising Actinic Keratosis Treatment" (PAKT) consensus reported that delivering patient-centric care may play a role in supporting better clinical outcomes and patient satisfaction with treatments for chronic dermatologic conditions such as AK, which require repeated cycles of treatment. Additionally, currently published guidance and recommendations were considered by the PAKT panel to be overly broad for managing ICPs with their unique and complex needs. Therefore, the "Personalising Actinic Keratosis Treatment for Immunocompromised Patients" (IM-PAKT) panel was established to build upon general recommendations from the PAKT consensus. The panel identified current gaps in guidance for AK care in ICPs, offered practical care approaches based on typical ICP scenarios, and highlighted the need to adapt AK management to optimize care and improve treatment outcomes in ICPs. In particular, dermatologists should establish collaborative and transparent relationships with patients' multidisciplinary teams to enhance overall care for patients' comorbidities: given their increased risk of progression to malignancy, earlier assessments/interventions and frequent follow-ups are vital.The panel also developed a novel "triage" tool outlining effective treatment follow-up and disease surveillance plans tailored to patients' risk profiles, guided by current clinical presentation and relevant medical history. Additionally, we present the panel's expert opinion on three fictional ICP scenarios to explain their decision-making process for assessing and managing typical ICPs that they may encounter in clinical practice.

Evaluation of the Parkinson's Remote Interactive Monitoring System in a Clinical Setting: Usability Study.

BACKGROUND: The fastest-growing neurological disorder is Parkinson disease (PD), a progressive neurodegenerative disease that affects 10 million people worldwide. PD is typically treated with levodopa, an oral pill taken to increase dopamine levels, and other dopaminergic agonists. As the disease advances, the efficacy of the drug diminishes, necessitating adjustments in treatment dosage according to the patient's symptoms and disease progression. Therefore, remote monitoring systems that can provide more detailed and accurate information on a patient's condition regularly are a valuable tool for clinicians and patients to manage their medication. The Parkinson's Remote Interactive Monitoring System (PRIMS), developed by PragmaClin Research Inc, was designed on the premise that it will be an easy-to-use digital system that can accurately capture motor and nonmotor symptoms of PD remotely. OBJECTIVE: We performed a usability evaluation in a simulated clinical environment to assess the ease of use of the PRIMS and determine whether the product offers suitable functionality for users in a clinical setting. METHODS: Participants were recruited from a user sign-up web-based database owned by PragmaClin Research Inc. A total of 11 participants were included in the study based on the following criteria: (1) being diagnosed with PD and (2) not being diagnosed with dementia or any other comorbidities that would make it difficult to complete the PRIMS assessment safely and independently. Patient users completed a questionnaire that is based on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale. Interviews and field notes were analyzed for underlying themes and topics. RESULTS: In total, 11 people with PD participated in the study (female individuals: n=5, 45%; male individuals: n=6, 55%; age: mean 66.7, SD 7.77 years). Thematic analysis of the observer's notes revealed 6 central usability issues associated with the PRIMS. These were the following: (1) the automated voice prompts are confusing, (2) the small camera is problematic, (3) the motor test exhibits excessive sensitivity to the participant's orientation and position in relation to the cameras, (4) the system poses mobility challenges, (5) navigating the system is difficult, and (6) the motor test exhibits inconsistencies and technical issues. Thematic analysis of qualitative interview responses revealed four central themes associated with participants' perspectives and opinions on the PRIMS, which were (1) admiration of purpose, (2) excessive system sensitivity, (3) video instructions preferred, and (4) written instructions disliked. The average system usability score was calculated to be 69.2 (SD 4.92), which failed to meet the acceptable system usability score of 70. CONCLUSIONS: Although multiple areas of improvement were identified, most of the participants showed an affinity for the overarching objective of the PRIMS. This feedback is being used to upgrade the current PRIMS so that it aligns more with patients' needs.

Summary of Research: Overall Survival with Osimertinib in Resected EGFR-Mutated NSCLC.

This is a summary of the original article ?Overall survival with osimertinib in resected EGFR-mutated NSCLC.Ë® Osimertinib blocks the activity of the epidermal growth factor receptor (EGFR) on cancer cells, causing cancer cell death and tumor shrinkage, and is an effective treatment for EGFR-mutated non-small cell lung cancer (NSCLC). The ADAURA study assessed the effects of osimertinib versus placebo in patients with EGFR-mutated (exon 19 deletion or L858R) early stage (IB-IIIA) NSCLC removed by surgery (resected). Previous results from ADAURA demonstrated that patients treated with osimertinib stayed alive and cancer-free (disease-free survival) significantly longer than patients who received placebo. Recent data showed the overall length of time patients were alive after starting treatment (overall survival). In both the primary stage II-IIIA and overall stage IB-IIIA populations, patients in the osimertinib group had a significant 51% reduction in the risk of death compared with the placebo group. The data demonstrated that osimertinib after surgery significantly improved overall survival in patients with resected, EGFR-mutated, stage IB-IIIA NSCLC.

Expanding access to magnetic resonance education through open-source web tutorials.

This study presents a tool that introduces the fundamental concepts of magnetic resonance (MR) by integrating related science, technology, engineering, arts, and mathematical (STEAM) topics in the form of games to improve the access to MR education.

Lurbinectedin in small cell lung cancer: real-world experience of a multicentre national early access programme.

BACKGROUND AND AIMS: Lurbinectedin is a novel oncogenic transcription inhibitor active in several cancers, including small cell lung cancer (SCLC). We aimed to describe the first Australian experience of the clinical efficacy and tolerability of lurbinectedin for the treatment of SCLC after progression on platinum-containing therapy. METHODS: Multicentre real-world study of individuals with SCLC initiating lurbinectedin monotherapy (3.2 mg/m2 three-weekly) on an early access programme between May 2020 and December 2021. Key outcomes were clinical utilisation, efficacy and tolerability. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Outcome data were collected within the AUstralian Registry and biObank of thoRacic cAncers (AURORA). RESULTS: Data were analysed for 46 individuals across seven sites. Lurbinectedin was given as second- (83%, 38/46) or subsequent- (17%, 8/46) line therapy, mostly with prior chemoimmunotherapy (87%, 40/46). We report dose modifications (17%, 8/46), interruptions/delays (24%, 11/46), high-grade toxicities (28%, 13/46) and hospitalisations (54%, 25/46) during active treatment. The overall response rate was 33% and the disease control rate was 50%. Six-month OS was 44% (95% confidence interval (CI): 29.0-57.1). Twelve-month OS was 15% (95% CI: 6.5-26.8). From lurbinectedin first dose, the median PFS was 2.5 months (95% CI: 1.8-2.9) and OS was 4.5 months (95% CI: 3.5-7.2). From SCLC diagnosis, the median OS was 12.9 months (95% CI: 11.0-17.2). Individuals with a longer chemotherapy-free interval prior to lurbinectedin had longer PFS and OS. CONCLUSION: This real-world national experience of lurbinectedin post-platinum chemotherapy and immunotherapy for individuals with SCLC was similar to that reported in clinical trials.

The Gárdos Channel and Piezo1 Revisited: Comparison between Reticulocytes and Mature Red Blood Cells.

The Gárdos channel (KCNN4) and Piezo1 are the best-known ion channels in the red blood cell (RBC) membrane. Nevertheless, the quantitative electrophysiological behavior of RBCs and its heterogeneity are still not completely understood. Here, we use state-of-the-art biochemical methods to probe for the abundance of the channels in RBCs. Furthermore, we utilize automated patch clamp, based on planar chips, to compare the activity of the two channels in reticulocytes and mature RBCs. In addition to this characterization, we performed membrane potential measurements to demonstrate the effect of channel activity and interplay on the RBC properties. Both the Gárdos channel and Piezo1, albeit their average copy number of activatable channels per cell is in the single-digit range, can be detected through transcriptome analysis of reticulocytes. Proteomics analysis of reticulocytes and mature RBCs could only detect Piezo1 but not the Gárdos channel. Furthermore, they can be reliably measured in the whole-cell configuration of the patch clamp method. While for the Gárdos channel, the activity in terms of ion currents is higher in reticulocytes compared to mature RBCs, for Piezo1, the tendency is the opposite. While the interplay between Piezo1 and Gárdos channel cannot be followed using the patch clamp measurements, it could be proved based on membrane potential measurements in populations of intact RBCs. We discuss the Gárdos channel and Piezo1 abundance, interdependencies and interactions in the context of their proposed physiological and pathophysiological functions, which are the passing of small constrictions, e.g., in the spleen, and their active participation in blood clot formation and thrombosis.

Four-year clinical update and treatment switching-adjusted outcomes with first-line nivolumab plus ipilimumab with chemotherapy for metastatic non-small cell lung cancer in the CheckMate 9LA randomized trial.

BACKGROUND: In CheckMate 9LA, nivolumab plus ipilimumab with chemotherapy prolonged overall survival (OS) versus chemotherapy regardless of tumor PD-L1 expression or histology. We report updated efficacy and safety in all randomized patients with a minimum 4-year follow-up and an exploratory treatment-switching adjustment analysis in all treated patients who received chemotherapy and subsequent immunotherapy. METHODS: Adults with stage IV/recurrent non-small cell lung cancer (NSCLC), no sensitizing EGFR/ALK alterations, and ECOG performance status ≤1 were randomized 1:1 to nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks with chemotherapy (two cycles) or chemotherapy (four cycles, with optional maintenance pemetrexed for the nonsquamous population). Assessments included OS, progression-free survival, and objective response rate. Exploratory analyses included efficacy by tumor PD-L1 expression and histology and in patients who discontinued nivolumab plus ipilimumab with chemotherapy due to treatment-related adverse events (TRAEs), and a treatment-switching adjustment analysis using inverse probability of censoring weighting. RESULTS: With a 47.9-month minimum follow-up for OS, nivolumab plus ipilimumab with chemotherapy continued to prolong OS over chemotherapy in all randomized patients (HR 0.74, 95% CI 0.63 to 0.87; 4-year OS rate: 21% versus 16%), regardless of tumor PD-L1 expression (HR (95% CI): PD-L1<1%, 0.66 (0.50 to 0.86) and ≥1%, 0.74 (0.60 to 0.92)) or histology (squamous, 0.64 (0.48 to 0.84) and non-squamous, 0.80 (0.66 to 0.97)). In patients who discontinued all components of nivolumab plus ipilimumab with chemotherapy due to TRAEs (n=61), the 4-year OS rate was 41%. With treatment-switching adjustment for the 36% of patients receiving subsequent immunotherapy in the chemotherapy arm, the estimated HR of nivolumab plus ipilimumab with chemotherapy versus chemotherapy was 0.66 (95% CI 0.55 to 0.80). No new safety signals were observed. CONCLUSIONS: In this 4-year update, patients treated with nivolumab plus ipilimumab with chemotherapy continued to have long-term, durable efficacy benefit over chemotherapy regardless of tumor PD-L1 expression and/or histology. A greater estimated relative OS benefit was observed after adjustment for subsequent immunotherapy use in the chemotherapy arm. These results further support nivolumab plus ipilimumab with chemotherapy as a first-line treatment for patients with metastatic/recurrent NSCLC, including those with tumor PD-L1<1% or squamous histology, populations with high unmet needs.