Immunostimulatory nucleic acid nanoparticles (NANPs) augment protective osteoblast and osteoclast type I interferon responses to Staphylococcus aureus.

Recalcitrant staphylococcal osteomyelitis may be due, in part, to the ability of Staphylococcus aureus to invade bone cells. However, osteoclasts and osteoblasts are now recognized to shape host responses to bacterial infection and we have recently described their ability to produce IFN-ß following S. aureus infection and limit intracellular bacterial survival/propagation. Here, we have investigated the ability of novel, rationally designed, nucleic acid nanoparticles (NANPs) to induce the production of immune mediators, including IFN-ß, following introduction into bone cells. We demonstrate the successful delivery of representative NANPs into osteoblasts and osteoclasts via endosomal trafficking when complexed with lipid-based carriers. Their delivery was found to differentially induce immune responses according to their composition and architecture via discrete cytosolic pattern recognition receptors. Finally, the utility of this nanoparticle technology was supported by the demonstration that immunostimulatory NANPs augment IFN-ß production by S. aureus infected bone cells and reduce intracellular bacterial burden.

Early intramuscular adrenaline administration is associated with improved survival from out-of-hospital cardiac arrest.

BACKGROUND: Early administration of adrenaline is associated with improved survival after out-of-hospital cardiac arrest (OHCA). Delays in vascular access may impact the timely delivery of adrenaline. Novel methods for administering adrenaline before vascular access may enhance survival. The objective of this study was to determine whether an initial intramuscular (IM) adrenaline dose followed by standard IV/IO adrenaline is associated with improved survival after OHCA. METHODS STUDY DESIGN: We conducted a before-and-after study of the implementation of an early, first-dose IM adrenaline EMS protocol for adult OHCAs. The pre-intervention period took place between January 2010 and October 2019. The post-intervention period was between November 2019 and May 2024. SETTING: Single-center urban, two-tiered EMS agency. PARTICIPANTS: Adult, nontraumatic OHCA meeting criteria for adrenaline use. INTERVENTION: Single dose (5 mg) IM adrenaline. All other care, including subsequent IV or IO adrenaline, followed international guidelines. MAIN OUTCOMES AND MEASURES: The primary outcome was survival to hospital discharge. Secondary outcomes were time from EMS arrival to the first dose of adrenaline, survival to hospital admission, and favorable neurologic function at discharge. RESULTS: Among 1450 OHCAs, 372 (29.9%) received IM adrenaline and 985 (70.1%) received usual care. Fifty-two patients received the first dose of adrenaline through the IV or IO route within the post-intervention period and were included in the standard care group analysis. Age was younger and bystander CPR was higher in the IM adrenaline group. All other characteristics were similar between IM and standard care cohorts. Time to adrenaline administration was faster for the IM cohort [(median 4.3 min (IQR 3.0-6.0) vs. 7.8 min (IQR 5.8-10.4)]. Compared with standard care, IM adrenaline was associated with improved survival to hospital admission (37.1% vs. 31.6%; aOR 1.37, 95% CI 1.06-1.77), hospital survival (11.0% vs 7.0%; aOR 1.73, 95% CI 1.10-2.71) and favorable neurologic status at hospital discharge (9.8% vs 6.2%; aOR 1.72, 95% CI 1.07-2.76). CONCLUSION: In this single-center before-and-after implementation study, an initial IM dose of adrenaline as an adjunct to standard care was associated with improved survival to hospital admission, survival to hospital discharge, and functional survival. A randomized controlled trial is needed to fully assess the potential benefit of IM adrenaline delivery in OHCA.

Examining the association between ethnicity and out-of-hospital cardiac arrest interventions in Salt Lake City, Utah.

Aims: Previous research has reported racial disparities in out-of-hospital cardiac arrest (OHCA) interventions, including bystander CPR and AED use. However, studies on other prehospital interventions are limited. The primary objective of this study was to investigate race/ethnic disparities in out-of-hospital cardiac arrest (OHCA) interventions: EMS response times, medication administration, and decisions for intra-arrest transport. The secondary objective was to evaluate differences in the provision of Bystander CPR (CPR) and application of AED. Methods: We retrospectively analyzed data from the Salt Lake City Fire Department (2010-2023). We included adults 18 years or older with EMS-treated OHCA. Race/ethnicity was categorized as White people, Asian people, Black people, Hispanic people, and others. We employed multivariable regression analysis to evaluate the association between race/ethnicity and the outcomes of interest. Results: Unadjusted analyses revealed no significant differences across ethnic groups in EMS response, medication administration, bystander CPR, or intra-arrest transport decisions. However, significant ethnic disparities were observed in Automated External Defibrillator (AED) utilization, Black people having the lowest rate (6.5%) and Asian people the highest (21.8%). The adjusted analysis found no significant association between race/ethnicity and all OHCA intervention measures, nor between race/ethnicity and survival outcomes. Conclusions: Our multivariable analysis found no statistically significant association between race/ethnicity and EMS response time, epinephrine administration, antiarrhythmic medication use, bystander CPR, AED intervention, or intra-arrest transport. These results imply regional variations in ethnic disparities in OHCA may not be consistent across all areas, warranting further research into disparities in other regions and additional influential factors like neighborhood conditions and socioeconomic status.

Clinical characteristics of women with HIV in the RESPOND cohort: A descriptive analysis and comparison to men.

BACKGROUND: Women with HIV are globally underrepresented in clinical research. Existing studies often focus on reproductive outcomes, seldom focus on older women, and are often underpowered to assess sex/gender differences. We describe CD4, HIV viral load (VL), clinical characteristics, comorbidity burden, and use of antiretroviral therapy (ART) among women with HIV in the RESPOND study and compare them with those of the men in RESPOND. METHODS: RESPOND is a prospective, multi-cohort collaboration including over 34 000 people with HIV from across Europe and Australia. Demographic and clinical characteristics, including CD4/VL, comorbidity burden, and ART are presented at baseline, defined as the latter of 1 January 2012 or enrolment into the local cohort, stratified by age and sex/gender. We further stratify men by reported mode of HIV acquisition, men who have sex with men (MSM) and non-MSM. RESULTS: Women account for 26.0% (n = 9019) of the cohort, with a median age of 42.2 years (interquartile range [IQR] 34.7-49.1). The majority (59.3%) of women were white, followed by 30.3% Black. Most women (75.8%) had acquired HIV heterosexually and 15.9% via injecting drug use. Nearly half (44.8%) were receiving a boosted protease inhibitor, 31.4% a non-nucleoside reverse transcriptase inhibitor, and 7.8% an integrase strand transfer inhibitor. The baseline year was 2012 for 73.2% of women and >2019 for 4.2%. Median CD4 was 523 (IQR 350-722) cells/µl, and 73.6% of women had a VL <200 copies/mL. Among the ART-naïve population, women were more likely than MSM but less likely than non-MSM (p < 0.001) to have CD4 <200 cells/µL and less likely than both MSM and non-MSM (p < 0.001) to have VL ≥100 000 copies/mL. Women were also more likely to be free of comorbidity than were both MSM and non-MSM (p < 0.0001). CONCLUSION: RESPOND women are diverse in age, ethnicity/race, CD4/VL, and comorbidity burden, with important differences relative to men. This work highlights the importance of stratification by sex/gender for future research that may help improve screening and management guidelines specifically for women with HIV.

Effects of amino resin-treated and heat-treated soybean meal on ruminal fermentation, nutrient digestion, and nitrogen partitioning in continuous culture.

The objective of this study was to evaluate the effects of amino resin-treated soybean meal (SBM) on ruminal fermentation, nutrient digestion, and N partitioning. Treatments were: (1) untreated solvent-extracted SBM, (2) amino resin-treated SBM (AR-SBM), and (3) heat-treated SBM (HT-SBM). The experimental design was arranged as a replicated 3 × 3 Latin square with 6 fermenters in a dual-flow continuous culture system. Treatments were randomly assigned to fermenters within a Latin square for each period. Each fermenter was fed 106 g/d of diet DM equally distributed in 2 feeding times daily at 0800 and 1800. Diets were formulated to contain 16% CP, 30% NDF, and 30% starch across treatments. The experiment consisted of 3 experimental periods, each lasting for 10 d. The first 7 d of each period were considered adaptation, and the last 3 d were used for sampling and data collection. On d 8 and 9, samples were collected for analysis of diurnal variation in concentrations of NH3-N, pH, and VFA during the first 8 h after feeding. On d 8, 9, and 10, samples were collected from the liquid and solid effluents accumulated over 24 h for analysis of daily averages of NH3-N and VFA pools, and true ruminal digestibility estimates. Data were analyzed using the MIXED procedure of SAS and significance was declared when P ≤ 0.05. The model included the fixed effect of treatment and random effects of square, period, and fermenter within square, while time and interaction treatment × time were included for analyses of diurnal variation, with time as repeated measures. Compared with SBM, the cultured ruminal contents of AR-SBM and HT-SBM had lower NH3-N concentrations, indicating lower microbial fermentation of protein. Molar proportions of isovalerate and isobutyrate were greater in SBM than AR-SBM and HT-SBM, with greater molar proportion of isobutyrate for SBM particularly during the first 2 h after feeding. Flow of NH3-N was greater for SBM compared with AR-SBM and HT-SBM, whereas NAN flow, bacterial N flow, and N efficiency were greater for AR-SBM and HT-SBM compared with SBM. Our results indicate that both the amino resin and heat treatments of SBM allow for similar decrease in microbial degradation of CP without limiting microbial protein synthesis in diets with 16% CP. Amino resin treatment may be effective in reducing microbial fermentation of protein in the rumen without adverse effects on digestibility or fermentation parameters as compared with SBM.

Use of high-pressure processing and low-temperature storage to extend the performance shelf-life of two types of String cheese.

The manufacturing method of String cheese is similar to Mozzarella, but the hot curd is extruded through narrow tubes or pipes, which align the protein fibers that provides the characteristic ability for consumers to pull strings from this cheese. Firmness is another important performance attribute for consumers who just bite into the String cheese without peeling off strings. There have only been a few studies on String cheese, but it is known that stringiness and firmness decrease during prolonged storage, which is a particular challenge for exporting String cheese. We explored 2 treatments to try to retain the stringiness and firmness of String cheese for longer storage periods. The techniques used were high pressure processing (HPP; 600 MPa for 3 min) and reduced storage temperature (0°C). In other cheese varieties, these techniques have helped extend the performance shelf-life. We tested these techniques using the 2 main types of commercial String cheese: direct acid (DASC) and cultured String cheese (CSC), that were obtained from 2 different manufacturing facilities. The DASC had higher fat (∼2.2%) and higher pH values (∼0.2 units) compared with the CSC. The CSC had higher protein content (∼3.4%), higher insoluble calcium content (∼8 mg insoluble Ca/g protein) and higher hardness values (∼4 N) compared with the DASC. Due to the compositional differences, the 2 varieties were statistically analyzed separately for all other attributes. In both cheese types, HPP caused an immediate reduction in stringiness, some solubilization of insoluble calcium, and a slight increase in the cheese pH values. HPP also caused a slight increase in the TPA hardness of the CSC samples until 14 d (possibly due to a slight increase in cheese pH). The use of the 0°C storage temperature reduced proteolysis and helped retain firmness during storage. Low temperature storage could help extend the performance shelf-life of String cheese by a couple of months, but HPP was not suitable as the process caused an immediate reduction in stringiness due to the disruption of the matrix induced by the HPP treatment.

Diagnosis, treatment, and surveillance of Diamond-Blackfan anaemia syndrome: international consensus statement.

Diamond-Blackfan anaemia (DBA), first described over 80 years ago, is a congenital disorder of erythropoiesis with a predilection for birth defects and cancer. Despite scientific advances, this chronic, debilitating, and life-limiting disorder continues to cause a substantial physical, psychological, and financial toll on patients and their families. The highly complex medical needs of affected patients require specialised expertise and multidisciplinary care. However, gaps remain in effectively bridging scientific discoveries to clinical practice and disseminating the latest knowledge and best practices to providers. Following the publication of the first international consensus in 2008, advances in our understanding of the genetics, natural history, and clinical management of DBA have strongly supported the need for new consensus recommendations. In 2014 in Freiburg, Germany, a panel of 53 experts including clinicians, diagnosticians, and researchers from 27 countries convened. With support from patient advocates, the panel met repeatedly over subsequent years, engaging in ongoing discussions. These meetings led to the development of new consensus recommendations in 2024, replacing the previous guidelines. To account for the diverse phenotypes including presentation without anaemia, the panel agreed to adopt the term DBA syndrome. We propose new simplified diagnostic criteria, describe the genetics of DBA syndrome and its phenocopies, and introduce major changes in therapeutic standards. These changes include lowering the prednisone maintenance dose to maximum 0·3 mg/kg per day, raising the pre-transfusion haemoglobin to 9-10 g/dL independent of age, recommending early aggressive chelation, broadening indications for haematopoietic stem-cell transplantation, and recommending systematic clinical surveillance including early colorectal cancer screening. In summary, the current practice guidelines standardise the diagnostics, treatment, and long-term surveillance of patients with DBA syndrome of all ages worldwide.

Enhancing Oncologists' Comfort with Serious Illness Conversations: The Impact of Serious Illness Conversation Guide (SICG) Training.

Providers oftentimes need to have difficult conversations with patients facing a poor prognosis. Research indicates that providers generally feel ill prepared for these conversations and that bad conversations may lead to more anxiety for patients. Communication skills development training programs have shown improvement in providers' skills. Our cancer center embarked on skills development training to help providers improve their skills and comfort in having serious illness conversations. During our phased approach, about 500 physicians and advanced practice providers in the Division of Oncology were trained for over a year. Their level of comfort with serious illness conversations was measured before and after the training by using both quantitative and qualitative methods. We found that mean and median comfort scores increased from pre-training to post-training. The findings suggest that the improved comfort and confidence observed among providers who undergo communications skills training can lead to better provider-patient communication, more patient-centered care, and improved patient satisfaction.

Pregnancy in Patients with the Fontan Operation.

Improved survival rates for patients with a Fontan circulation has allowed more women with this complex cardiac physiology to contemplate pregnancy. However, pregnancy in women with a Fontan circulation is associated with a high risk of adverse maternal and fetal outcomes, high rates of miscarriage and preterm delivery. Factors associated with a successful pregnancy outcome are: younger age, normal body weight, absence of significant functional limitation, no Fontan-related complications, and well-functioning single ventricle physiology. Appropriate care with timely preconception counselling and regular, frequent clinical reviews by a multidisciplinary team based at a tertiary centre, improves the chance of a successful pregnancy. Empowerment of patients with education on their specific congenital cardiac condition and its projected trajectory, helps them make informed choices regarding their health, reproductive choices and assists them to achieve their life goals.

Observations and properties of the first laboratory fusion experiment to exceed a target gain of unity.

An indirect-drive inertial fusion experiment on the National Ignition Facility was driven using 2.05 MJ of laser light at a wavelength of 351 nm and produced 3.1±0.16 MJ of total fusion yield, producing a target gain G=1.5±0.1 exceeding unity for the first time in a laboratory experiment [Phys. Rev. E 109, 025204 (2024)10.1103/PhysRevE.109.025204]. Herein we describe the experimental evidence for the increased drive on the capsule using additional laser energy and control over known degradation mechanisms, which are critical to achieving high performance. Improved fuel compression relative to previous megajoule-yield experiments is observed. Novel signatures of the ignition and burn propagation to high yield can now be studied in the laboratory for the first time.

The development of a nurse-led preoperative anaesthesia screening tool by Delphi consensus.

BACKGROUND: Low- and middle-income countries have a critical shortage of specialist anaesthetists. Most patients arriving for surgery are of low perioperative risk. Without immediate access to preoperative specialist care, an appropriate interim strategy may be to ensure that only high-risk patients are seen preoperatively by a specialist. Matching human resources to the burden of disease with a nurse-administered pre-operative screening tool to identify high-risk patients who might benefit from specialist review prior to the day of surgery may be an effective strategy. OBJECTIVE: To develop a nurse-administered preoperative anaesthesia screening tool to identify patients who would most likely benefit from a specialist review before the day of surgery, and those patients who could safely be seen by the anaesthetist on the day of surgery. This would ensure adequate time for optimisation of high-risk patients preoperatively and limit avoidable day-of-surgery cancellations. METHODS: A systematic review was conducted to identify preoperative screening questions for use in a three-round Delphi consensus process. A panel of 16 experienced full-time clinical anaesthetists representing all university-affiliated anaesthesia departments in South Africa participated to define a nurses' screening tool for preoperative assessment. RESULTS: Ninety-eight studies were identified, which generated 79 questions. An additional 14 items identified by the facilitators were added to create a list of 93 questions for the first round. The final screening tool consisted of 81 questions, of which 37 were deemed critical to identify patients who should be seen by a specialist prior to the day of surgery. CONCLUSION: A structured nurse-administered preoperative screening tool is proposed to identify high-risk patients who are likely to benefit from a timely preoperative specialist anaesthetist review to avoid cancellation on the day of surgery.

Antibody elution with 2-me/SDS solution: Uses for multi-layer immunohistochemical analysis of wholemount preparations of human colonic myenteric plexus.

Indirect immunofluorescence is usually restricted to 3-5 markers per preparation, limiting analysis of coexistence. A solution containing 2-mercaptoethanol and sodium dodecyl sulfate (2-ME/SDS) can elute indirect immunofluorescence labelling (i.e. primary antisera followed by fluorophore-conjugated secondary antisera) and has been used for sequential staining of sections. The aim of this study was to test whether 2-ME/SDS is effective for eluting indirect immunofluorescent staining (with primary antisera visualised by fluorophore-coupled secondary antisera) in wholemount preparations. We also analysed how 2-ME/SDS may work and used this understanding to devise additional uses for immunofluorescence in the nervous system. 2-ME/SDS appears to denature unfixed proteins (including antisera used as reagents) but has much less effect on antigenicity of formaldehyde-fixed epitopes. Moieties linked by strong biotin-streptavidin bonds are highly resistant to elution by 2-ME/SDS. Two primary antisera raised in the same species can be applied without spurious cross-reactivity, if a specific order of labelling is followed. The first primary antiserum is followed by a biotinylated secondary, then a tertiary of fluorophore-conjugated streptavidin. The preparation is then exposed to 2-ME/SDS, which has minimal impact on labelling by the first primary/secondary/tertiary combination. However, when this is followed by a second primary antiserum (raised in the same species), followed by a fluorophore-conjugated secondary antiserum, the intervening 2-ME/SDS exposure prevents cross-reactivity between primary and secondary antisera of the two layers. A third property of 2-ME/SDS is that it reduces lipofuscin autofluorescence, although it also raises background fluorescence and strongly enhances autofluorescence of erythrocytes. In summary, 2-ME/SDS is easy to use, cost-effective and does not require modified primary antisera. It can be used as the basis of a multi-layer immunohistochemistry protocol and allows 2 primary antisera raised in the same species to be used together.

Immunostimulation of Fibrous Nucleic Acid Nanoparticles Can be Modulated through Aptamer-Based Functional Moieties: Unveiling the Structure-Activity Relationship and Mechanistic Insights.

Fibrous nanomaterials containing silica, titanium oxide, and carbon nanotubes are notoriously known for their undesirable inflammatory responses and associated toxicities that have been extensively studied in the environmental and occupational toxicology fields. Biopersistance and inflammation of "hard" nanofibers prevent their broader biomedical applications. To utilize the structural benefits of fibrous nanomaterials for functionalization with moieties of therapeutic significance while preventing undesirable immune responses, researchers employ natural biopolymers─RNA and DNA─to design "soft" and biodegradable nanomaterials with controlled immunorecognition. Nucleic acid nanofibers have been shown to be safe and efficacious in applications that do not require their delivery into the cells such as the regulation of blood coagulation. Previous studies demonstrated that unlike traditional therapeutic nucleic acids (e.g., CpG DNA oligonucleotides) nucleic acid nanoparticles (NANPs), when used without a carrier, are not internalized by the immune cells and, as such, do not induce undesirable cytokine responses. In contrast, intracellular delivery of NANPs results in cytokine responses that are dependent on the physicochemical properties of these nanomaterials. However, the structure-activity relationship of innate immune responses to intracellularly delivered fibrous NANPs is poorly understood. Herein, we employ the intracellular delivery of model RNA/DNA nanofibers functionalized with G-quadruplex-based DNA aptamers to investigate how their structural properties influence cytokine responses. We demonstrate that nanofibers' scaffolds delivered to the immune cells using lipofectamine induce interferon response via the cGAS-STING signaling pathway activation and that DNA aptamers incorporation shields the fibers from recognition by cGAS and results in a lower interferon response. This structure-activity relationship study expands the current knowledge base to inform future practical applications of intracellularly delivered NANPs as vaccine adjuvants and immunotherapies.

Translational insights and overall survival in the U31402-A-U102 study of patritumab deruxtecan (HER3-DXd) in EGFR-mutated NSCLC.

BACKGROUND: Human epidermal growth factor receptor 3 (HER3) is broadly expressed in non-small-cell lung cancer (NSCLC) and is the target of patritumab deruxtecan (HER3-DXd), an antibody-drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. U31402-A-U102 is an ongoing phase I study of HER3-DXd in patients with advanced NSCLC. Patients with epidermal growth factor receptor (EGFR)-mutated NSCLC that progressed after EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy (PBC) who received HER3-DXd 5.6 mg/kg intravenously once every 3 weeks had a confirmed objective response rate (cORR) of 39%. We present median overall survival (OS) with extended follow-up in a larger population of patients with EGFR-mutated NSCLC and an exploratory analysis in those with acquired genomic alterations potentially associated with resistance to HER3-DXd. PATIENTS AND METHODS: Safety was assessed in patients with EGFR-mutated NSCLC previously treated with EGFR TKI who received HER3-DXd 5.6 mg/kg; efficacy was assessed in those who also had prior PBC. RESULTS: In the safety population (N = 102), median treatment duration was 5.5 (range 0.7-27.5) months. Grade ≥3 adverse events occurred in 76.5% of patients; the overall safety profile was consistent with previous reports. In 78/102 patients who had prior third-generation EGFR TKI and PBC, cORR by blinded independent central review (as per RECIST v1.1) was 41.0% [95% confidence interval (CI) 30.0% to 52.7%], median progression-free survival was 6.4 (95% CI 4.4-10.8) months, and median OS was 16.2 (95% CI 11.2-21.9) months. Patients had diverse mechanisms of EGFR TKI resistance at baseline. At tumor progression, acquired mutations in ERBB3 and TOP1 that might confer resistance to HER3-DXd were identified. CONCLUSIONS: In patients with EGFR-mutated NSCLC after EGFR TKI and PBC, HER3-DXd treatment was associated with a clinically meaningful OS. The tumor biomarker characterization comprised the first description of potential mechanisms of resistance to HER3-DXd therapy.

Single radio frequency bucket injection in the 88-Inch Cyclotron using a pulsed high voltage chopper.

A single radio frequency bucket of the 88-Inch Cyclotron is filled using a fast chopper located in the axial line. The bucket then accelerates until it reaches the deflector, at which point, it is extracted as a train of bunches. This phenomenon can be attributed to the characteristic multi-turn extraction of the cyclotron and, by simplifying the complex dynamics of a cyclotron, corresponds to the conceptual transfer function of the cyclotron. The confirmation of the single radio frequency bucket injection was achieved by operating the cyclotron in the third harmonic mode and observing the absence of intermediate bunches during the multiple-bunch extraction.

Long-term medication for ADHD (LMA) trial: 2-year prospective observational study in children and adolescents. Core symptoms, daily functioning, and comorbidity outcomes.

More knowledge is needed about long-term ADHD medication and symptom, daily functioning, comorbidity, and tolerability outcomes. This "Long-term Medication for ADHD (LMA) trial" was a prospective observational 2-year trial in children and adolescents aged 6-18 years (extension of 1-year trial). Participants met criteria for DSM-5 ADHD (inattentive or combined), with complex comorbidities; autism spectrum disorder (31%), autistic traits (24%), oppositional symptoms (59%), anxiety (32%), dyslexia/language disorder (16%), borderline intellectual functioning (17%). Medication was individually tailored and followed-up at clinical visits (1, 2, 3, 6, 12, 18, 24 months). Primary outcome: Clinical Global Impression-Severity and Improvement scales (CGI-S, CGI-I). Secondary outcomes: Investigator-rated ADHD-Rating Scale, Weiss Functional Impairment Rating Scale-Parent report (WFIRS-P; Family, School Learning and Behavior, Life Skills, Self-Concept, Social Activities, and Risky Activities domains), comorbidity symptoms and adverse events (AEs). One hundred twenty-eight participants were enrolled (1-year trial only n = 27, LMA trial n = 101). Of these 29 (23%) discontinued, mainly due to AEs (n = 7), moving (n = 7), or no longer needing medication (n = 6). Main AEs were poor appetite, low mood, anxiety, irritability, fatigue. Improvements from baseline to 2 years were large in CGI-S (effect size (ES) 2.28), ADHD-RS (ES 2.06), and moderate to large in WFIRS-P (ES total 0.73, learning 0.4, family 0.67). Overall, the trial showed robust and sustained improvements in ADHD symptom severity and daily functioning over a period of 2 years of ADHD medication in children and adolescents with ADHD and complex comorbidities. Most AEs were mild. Comorbidity symptoms were improved after 1 year, particularly oppositional symptoms, depression, and anxiety.

SAPPHIRE: phase III study of sitravatinib plus nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer.

BACKGROUND: Checkpoint inhibitor (CPI) therapy revolutionized treatment for advanced non-small-cell lung cancer (NSCLC); however, most patients progress due to primary or acquired resistance. Sitravatinib is a receptor tyrosine kinase inhibitor that can shift the immunosuppressive tumor microenvironment toward an immunostimulatory state. Combining sitravatinib with nivolumab (sitra + nivo) may potentially overcome initial CPI resistance. PATIENTS AND METHODS: In the phase III SAPPHIRE study, patients with advanced non-oncogenic driven, nonsquamous NSCLC who initially benefited from (≥4 months on CPI without progression) and subsequently experienced disease progression on or after CPI combined with or following platinum-based chemotherapy were randomized 1 : 1 to sitra (100 mg once daily administered orally) + nivo (240 mg every 2 weeks or 480 mg every 4 weeks administered intravenously) or docetaxel (75 mg/m2 every 3 weeks administered intravenously). The primary endpoint was overall survival (OS). The secondary endpoints included progression-free survival (PFS), objective response rate (ORR), clinical benefit rate (CBR), duration of response (DOR; all assessed by blinded independent central review), and safety. RESULTS: A total of 577 patients included randomized: sitra + nivo, n = 284; docetaxel, n = 293 (median follow-up, 17.1 months). Sitra + nivo did not significantly improve OS versus docetaxel [median, 12.2 versus 10.6 months; hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.70-1.05; P = 0.144]. The median PFS was 4.4 versus 5.4 months, respectively (HR 1.08, 95% CI 0.89-1.32; P = 0.452). The ORR was 15.6% for sitra + nivo and 17.2% for docetaxel (P = 0.597); CBR was 75.5% and 64.5%, respectively (P = 0.004); median DOR was 7.4 versus 7.1 months, respectively (P = 0.924). Grade ≥3 treatment-related adverse events were observed in 53.0% versus 66.7% of patients receiving sitra + nivo versus docetaxel, respectively. CONCLUSIONS: Although median OS was numerically longer with sitra + nivo, the primary endpoint was not met in patients with previously treated advanced nonsquamous NSCLC. The safety profiles demonstrated were consistent with previous reports.