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.

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.

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.

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.

Partial replacement of soybean meal with microalgae biomass on in vitro ruminal fermentation may reduce ruminal protein degradation.

The objective of this study was to evaluate the effects of partially replacing soybean meal (SBM) with algal sources on in vitro ruminal fermentation. Using 6 fermenters in a 3 × 3 replicated Latin square with 3 periods of 10 d each, we tested 3 treatments: a control diet (CRT) with SBM at 17.8% of the diet dry matter (DM); and 50% SBM biomass replacement with either Chlorella pyrenoidosa (CHL); or Spirulina platensis (SPI). The basal diet was formulated to meet the requirements of a 680-kg Holstein dairy cow producing 45 kg/d of milk with 3.5% fat and 3% protein. All diets had a similar nutritional composition (16.0% CP; 34.9% NDF; 31.0% starch, DM basis) and fermenters were provided with 106 g DM/d split into 2 portions. After 7 d of adaptation, samples were collected for 3 d of each period for analyses of ruminal fermentation at 0, 1, 2, 4, 6, and 8 h after morning feeding for evaluation of the ruminal fermentation kinetics. For the evaluation of the daily production of total metabolites and for the evaluation of nutrient degradability, samples from the effluent containers were collected daily. Statistical analysis was performed with the MIXED procedure of SAS with treatment, time, and their interactions considered as fixed effects; day, square, and fermenter were considered as random effects. Orthogonal contrasts (CRT vs. algae; and CHL vs. SPI) were used to depict the treatment effect, and significance was declared when P ≤ 0.05. Fermenters that received algae-based diets had a greater propionate molar concentration and molar proportion when compared with the fermenters fed CRT diets. In addition, those algae-fed fermenters had lower branched short-chain fatty acids (BSCFA) and isoacids (IA), which are biomarkers of ruminal protein degradation, along with lower ammonia (NH3-N) concentration and greater nonammonia nitrogen (NAN). When contrasting with fermenters fed SPI-diets, fermenters fed based CHL-diets had a lower molar concentration of BSCFA and IA, along with lower NH3-N concentration and flow, and greater NAN, bacterial nitrogen flow, and efficiency of nitrogen utilization. Those results indicate that CHL protein may be more resistant to ruminal degradation, which would increase efficiency of nitrogen utilization. In summary, partially replacing SBM with algae biomass, especially with CHL, is a promising strategy to improve the efficiency of nitrogen utilization, due to the fact that fermenters fed CHL-based diets resulted in a reduction in BSCFA and IA, which are markers of protein degradation, and it would improve the efficiency of nitrogen utilization. However, further validation using in vivo models are required.

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.

National Diagnostic Working Group (NDWG) for inertial confinement fusion (ICF)/high-energy density (HED) science: The whole exceeds the sum of its parts.

The National Diagnostic Working Group (NDWG) has led the effort to fully exploit the major inertial confinement fusion/high-energy density facilities in the US with the best available diagnostics. These diagnostics provide key data used to falsify early theories for ignition and suggest new theories, recently leading to an experiment that exceeds the Lawson condition required for ignition. The factors contributing to the success of the NDWG, collaboration and scope evolution, and the methods of accomplishment of the NDWG are discussed in this Review. Examples of collaborations in neutron and gamma spectroscopy, x-ray and neutron imaging, x-ray spectroscopy, and deep-ultraviolet Thomson scattering are given. An abbreviated history of the multi-decade collaborations and the present semiformal management framework is given together with the latest National Diagnostic Plan.

Diagnosing the origin and impact of low-mode asymmetries in ignition experiments at the National Ignition Facility.

Inertial confinement fusion ignition requires high inflight shell velocity, good energy coupling between the hotspot and shell, and high areal density at peak compression. Three-dimensional asymmetries caused by imperfections in the drive symmetry or target can grow and damage the coupling and confinement. Recent high-yield experiments have shown that low-mode asymmetries are a key degradation mechanism and contribute to variability. We show the experimental signatures and impacts of asymmetry change with increasing implosion yield given the same initial cause. This letter has implications for improving robustness to a key degradation in ignition experiments.

'Whether it's your weapon or not, it's your home': US military spouse perspectives on personal firearm storage.

INTRODUCTION: In the USA, an estimated 45% of veterans personally own firearms. Firearm access increases the risk of suicide, so suicide prevention efforts in the US Department of Defense (DoD) focus on lethal means safety, including reducing firearm access. Spouse input may enhance effective messaging and intervention delivery of lethal means safety. This study used qualitative methods to explore the perspectives of military spouses or partners on personal firearm storage, including at-home decisions, on-base storage and existing messaging from the DoD. MATERIALS AND METHODS: Qualitative data were obtained using 1:1 interviews and focus groups with spouses/partners of US military service members (active duty, Reserve, National Guard, recently separated from the military) and representatives from military support organisations. Sessions focused on personal firearm storage (at home or on military installations) and military messaging around secure firearm storage and firearm suicide prevention. Data were analysed using a team-based, mixed deductive-inductive approach. RESULTS: Across 56 participants (August 2022-March 2023), the themes were variability in current home firearm storage and spousal participation in decision-making; uncertainty about firearm storage protocols on military installations; mixed awareness of secure firearm storage messaging from the military; and uncertainty about procedures or protocols for removing firearm access for an at-risk person. CONCLUSION: US military spouses are important messengers for firearm safety and suicide prevention, but they are currently underutilised. Tailored prevention campaigns should consider spousal dynamics and incorporate education about installation procedures.

The Impact of Varying Nipple Properties on Infant Feeding Physiology and Performance Throughout Ontogeny in a Validated Animal Model.

Infant feeding requires successful interactions between infant physiology and the maternal (or bottle) nipple. Within artificial nipples, there is variation in both nipple stiffness and flow rates, as well as variation in infant physiology as they grow and mature. However, we have little understanding into how infants interact with variable nipple properties to generate suction and successfully feed. We designed nipples with two different stiffnesses and hole sizes and measured infant feeding performance through ontogeny using a pig model. We evaluated their response to nipple properties using high-speed X-Ray videofluoroscopy. Nipple properties substantially impacted sucking physiology and performance. Hole size had the most profound impact on the number of sucks infants took per swallow. Pressure generation generally increased with age, especially in nipples where milk acquisition was more difficult. However, most strikingly, in nipples with lower flow rates the relationship between suction generation and milk acquisition was disrupted. In order to design effective interventions for infants with feeding difficulties, we must consider how variation in nipple properties impacts infant physiology in a targeted manner. While reducing flow rate may reduce the frequency an infant aspirates, it may impair systems involved in sensorimotor integration.