Smallholder farmers' challenges and opportunities: Implications for agricultural production, environment and food security.

In an era of growing environmental, socioeconomic, and market uncertainties, understanding the adaptive strategies of smallholder farmers is paramount for sustainable agricultural productivity and environmental management efforts. We adopted a mixed-methods approach to investigate the adaptive strategies of smallholders in Northwest Cambodia. Our methodology included downscaled climate projections to project future climate conditions and scenarios, household surveys to collect detailed demographic and socioeconomic data, crop monitoring and record-keeping to gather data on productivity and profitability, and semi-structured interviews to obtain qualitative insights on constraints and adaptation. Our analyses revealed that all smallholders are increasingly vulnerable to climate change which projections reveal will result in more intense and extreme weather events. Specifically, 92% of respondents reported reductions in household income, and 63% indicated the necessity to cut household expenses, which negatively affect agricultural productivity, as evidenced by 33% of respondents reporting declining crop yields and 10% experiencing food shortages. We also uncovered significant differences in farming strategies to mitigate vulnerability among distinct household clusters. Some households prioritise maximising yields through high-expense production strategies, while others focus on optimising inputs to enhance profit-margins, indirectly minimising their environmental impact. These varying strategies have different implications for poverty, food security, and the environment, but were doing very little to mitigate overall vulnerability. To enhance the adaptive capacity of smallholders, policies should target interventions that balance economic growth with environmental sustainability, tailored to the specific needs of different farmer and household types. Promoting the adoption of climate-resilient agricultural practices, investing in water management infrastructure, enhancing access to timely and accurate climate information, and implementing social protection measures are strongly recommended.

On-demand green/red light-responsive self-doped SnO2 nanoparticles for single/multi-color transitioning fabrics.

Semiconductor/redox-based dual light-induced color switching systems (LCSs) with a visible light response at different wavelengths are highly sought after for efficient redox reactions. In this work, Sn2+ self-doped SnO2 has been designed as nanophotocatalysts for preparing visible light-responsive inks/fabrics with single/multi-color abilities. The self-doping of SnO2 nanoparticles results in the formation of oxygen vacancies due to charge compensation effects leading to electron-driven photoreduction and photooxidation of LSC inks. By mixing SnO2-x nanoparticles dispersions with specific redox-sensitive dyes can lead to the creation of well-designed sets of visible light-responsive semiconductor-driven LCS systems with both single-color (RGB) and multi-color (violet and green) changes. The exposure of LCS inks to green (550 nm) light culminates in the rapid photoreduction of the inks to decolorized state, while red (660 nm) light initiates the photooxidation in air. The combination of the LCS inks with -OH-rich polymers can be coated on the hydrophobic surface of the layered fabric to produce photo-responsive fabrics with single/multi-color response. The interaction of green light with the semiconductor-driven LCS systems allows the remote photo-printing of different images/letters on the LCS fabrics. Spontaneous erasure can be achieved by red light with high stability and repeatability (>35 cycles). The research in this paper provides new perspectives and insights for the development of new color-changing materials with potential applications as light-activated sensors and display units.

Are changes in pain intensity related to changes in balance control in individuals with chronic non-specific low back pain? A systematic review and meta-analysis.

PURPOSE: The aim of this study is to summarize the evidence regarding whether pain reduction in individuals with chronic non-specific low back pain (CNSLBP) following conservative interventions is related to corresponding improvements in balance control. METHODS: Randomized controlled trials were identified from 5 databases (MEDLINE, Cochrane Library, Embase, Web of Science, and PsycINFO). Two reviewers independently screened and identified relevant studies that investigated the effects of nonsurgical or nonpharmacological CNSLBP treatments on both pain intensity and balance control. Meta-regression analyses were performed to establish the associations between post-treatment changes in these 2 variables. RESULTS: 31 studies involving 1280 participants with CNSLBP were included. Moderate-quality evidence suggested that pain reduction was associated with and explained 34%-45% of decreases in body sway, as measured by center-of-pressure (CoP) area and CoP velocity with eyes open. However, no significant association was observed between pain reduction and CoP area or velocity in anteroposterior/mediolateral directions. Similarly, there was no significant association between pain reduction and CoP distance or radius. Low-quality evidence indicated that pain relief explained a 15% improvement in one-leg stance with eyes open but not in the eyes-closed condition. Additionally, very low-quality evidence suggested that pain relief explained a 44% decrease in the static anteroposterior stability index with eyes closed but not in the eyes-open, mediolateral, or overall conditions. Furthermore, low-quality evidence indicated that reduced pain was associated with and accounted for 25%-43% of the improved composite and posteromedial scores of the star-excursion balance test, rather than the anterior and posterolateral scores. CONCLUSION: Depending on the type of balance assessment, pain relief following conservative interventions may slightly to moderately enhance balance control in individuals with CNSLBP. Clinicians should pay close attention to the balance control in patients with CNSLBP, particularly among older adults.

Growth of sulfur-doped bismuth oxybromide nanosheets on carbon fiber cloth for photocatalytically purifying antibiotic wastewater.

Bismuth oxybromide (BiOBr) nanomaterials are well-known efficient powder-shaped photocatalyst for degrading antibiotic wastewater, but their practical applications have been limited by unsatisfactory photo-absorption, weak photocatalytic activity and poor recyclability. To address these issues, we demonstrate that the growing of S-doped BiOBr nanosheets on carbon fiber cloth (CFC) can lead to efficient photocatalysis with recyclable features. With carbon fiber cloth as the substrate, S-doped BiOBr (BiOBr-Sx) nanosheets (diameter: ∼500 nm, thicknesses: ∼5-90 nm) was prepared by solvothermal method with thiourea as dopant. With the increase of thiourea (0-0.2 g) in the precursor solution, BiOBr-Sx nanosheets exhibit a significant shift in the photo-absorption edge from 420 to 461 nm and decreased thicknesses from 90 to 5 nm, accompanying by the increased proportion of (010) exposed surface. Amony them, CFC/BiOBr-S0.5 can degrade various contaminants (such as 98.7 % levofloxacin (LVFX), 95.6 % ciprofloxacin (CIP) and 95.9 % tetracycline (TC)) with most degradation efficiency within 120 min of visible light irradiation, which are 1.6, 1.9 and 1.4 times than that of CFC/BiOBr (61.4 % LVFX, 49.5 % CIP and 67.1 % TC), respectively. Significantly, when CFC/BiOBr-S0.05 photocatalytic fabric is combined with a multi-stage flow device to treat the flowing wastewater (10 mg/L LVFX, rate: 1 L/h), 91.0 % LVFX can be degraded after tenth grade. Therefore, this study not only demonstrates the controllable preparation of S-doped BiOBr nanosheets with different thickness on CFC but also highlights the practical applications of fabric-based photocatalysts for purifying the flowing sewage efficiently.

Survey of pediatric massive transfusion protocol practice at United States level I trauma centers: An AABB Pediatric Transfusion Medicine Subsection study.

BACKGROUND: Trauma remains the leading cause of pediatric mortality in the United States. Although use of massive transfusion protocols (MTPs) in this population is widespread, optimal pediatric resuscitation is not well established. We sought to assess contemporary pediatric MTP practice in the United States. STUDY DESIGN AND METHODS: A web-based survey was designed by the Association for the Advancement of Blood & Biotherapies (AABB) Pediatric Transfusion Medicine Subsection and distributed to select American College of Surgeons (ACS) Level I Verified pediatric trauma centers. The survey assessed current MTP policy, implementation, and recent changes in practice. RESULTS: Response rate was 55% (22/40). Almost half of the respondents were from the South. The median RBC:plasma ratio was 1 (interquartile range 1-1.5). Protocolized fibrinogen supplementation was common while integration of antifibrinolytic therapy into MTPs was infrequent. Viscoelastic testing (VET) was available at most sites, 71% (15/21, one site did not respond), and was generally utilized on an ad-hoc basis. Roughly, a third of sites had changed their MTP in the past 3 years due to blood supply issues, and about a third reported having group O Whole Blood on-site. CONCLUSION: MTP practice is similar throughout the United States. Though fibrinogen supplementation is common-other emerging interventions such as antifibrinolytic therapy or utilization of routine viscoelastic testing-are not widespread. Pediatric transfusion medicine experts must continue to follow practice change, as contemporary large trials begin to characterize new supportive modalities to optimize resuscitation in pediatric trauma patients.

Assessment of the HIV Enhanced Access Testing in the Emergency Department (HEATED) program in Nairobi, Kenya: a quasi-experimental prospective study.

BACKGROUND: Persons seeking emergency injury care are often from higher-risk and underserved key populations (KPs) and priority populations (PPs) for HIV programming. While facility-based HIV Testing Services (HTS) in Kenya are effective, emergency department (ED) delivery is limited, despite the potential to reach underserved persons. METHODS: This quasi-experimental prospective study evaluated implementation of the HIV Enhanced Access Testing in Emergency Departments (HEATED) at Kenyatta National Hospital ED in Nairobi, Kenya. The HEATED program was designed as a multi-component intervention employing setting appropriate strategies for HIV care sensitization and integration, task shifting, resource reorganization, linkage advocacy, skills development and education to promote ED-HTS with a focus on higher-risk persons. KPs included sex workers, gay men, men who have sex with men, transgender persons and persons who inject drugs. PPs included young persons (18-24 years), victims of interpersonal violence, persons with hazardous alcohol use and persons never HIV tested. Data were obtained from systems-level records, enrolled injured patient participants and healthcare providers. Systems and patient-level data were collected during a pre-implementation period (6 March - 16 April 2023) and post-implementation (period 1, 1 May - 26 June 2023). Additional, systems-level data were collected during a second post-implementation (period 2, 27 June - 20 August 2023). HTS data were evaluated as facility-based HIV testing (completed in the ED) and distribution of HIV self-tests independently, and aggregated as ED-HTS. Evaluation analyses were completed across reach, effectiveness, adoption, implementation and maintenance framework domains. RESULTS: All 151 clinical staff were reached through trainings and sensitizations on the HEATED program. Systems-level ED-HTS among all presenting patients increased from 16.7% pre-implementation to 23.0% post-implementation periods 1 and 2 (RR = 1.31, 95% CI: 1.21-1.43; p < 0.001). Among 605 enrolled patient participants, facilities-based HTS increased from 5.7% pre-implementation to 62.3% post-implementation period 1 (RR = 11.2, 95%CI: 6.9-18.1; p < 0.001). There were 440 (72.7%) patient participants identified as KPs (5.6%) and/or PPs (65.3%). For enrolled KPs/PPs, facilities-based HTS increased from 4.6% pre-implementation to 72.3% post-implementation period 1 (RR = 13.8, 95%CI: 5.5-28.7, p < 0.001). Systems and participant level data demonstrated successful adoption and implementation of the HEATED program. Through 16 wk post-implementation a significant increase in ED-HTS delivery was maintained as compared to pre-implementation. CONCLUSIONS: The HEATED program increased overall ED-HTS and augmented delivery to KPs/PPs, suggesting that broader implementation could improve HIV services for underserved persons already in contact with health systems.

First Report of Impatiens Necrotic Spot Virus (INSV) Infecting Lettuce in Mexico.

Impatiens necrotic spot virus (INSV; Order Bunyavirales, Family Tospoviridae) is transmitted by several thrips species and has emerged as an important pathogen of lettuce (Lactuca sativa) in several countries (Beris et al., 2020 and Hasegawa & Del Pozo-Valdivia, 2023). In 2023, a total of 22,092 hectares of lettuce were planted in Mexico, with a total production of 523,739 tons (Agri-Food and Fisheries Information Service, 2024). In the last several years, increased outbreaks of a disease showing virus-like symptoms have emerged in lettuce in central Mexico. In all cases, plants exhibited symptoms of yellowing, brown necrotic spots and ringspots on the leaves and midribs, and reduced growth. In fall 2023, symptoms were observed in 12 iceberg lettuce fields, with incidences between 5-70% in the municipality of Tenango del Valle, in the state of Mexico. 18 plants collected from 6 fields were initially tested for the presence of two thrips-transmitted viruses, INSV and tomato spotted wilt virus (TSWV) using ImmunoStrips (Agdia Inc., Elkhart, Indiana), which indicated positive results for INSV in 16 plants and TSWV in 2 plants. None of the plants tested positive for both viruses. Follow up sampling was conducted, which included a total of 17 symptomatic lettuce plants from three fields in October 2023, while an additional 11 lettuce plants were collected from Tepeaca, in the neighboring state of Puebla in March 2024. DAS-ELISA confirmed the presence of INSV in 13/17 plants and TSWV in 2/17 plants from Tenango del Valle, while only INSV was detected in the 11 plants from Tepeaca. Based on ELISA, none of the lettuce samples were co-infected by INSV and TSWV, which was similarly observed in California and Greece (Koike et al., 2008 and Beris et al., 2020). Initially, RNA was purified from 3 plants (two from Tenango del Valle, one from Tepeaca) reverse-transcribed, and PCR amplified with primers to the N gene of the INSV S RNA, as previously described (Hasegawa et al., 2022). All three reactions produced a single expected amplicon of 524 bp and were confirmed by bi-directional Sanger sequencing (MCLab, South San Francisco, CA). To obtain the full-length sequences for the N and NSm genes, RNA from a fourth sample (Tenango del Valle) was amplified with primers (Kuo et al., 2014), and Sanger sequenced. The 789 bp N gene (PP726902) shared >99% nucleotide and amino acid identity to the corresponding region of the INSV isolate from orchid in California (KF926828), while the 912 bp NSm gene (PP726901) shared >98% nucleotide and amino acid identity to the INSV isolate from basil in Washington (KX790322). Additionally, all four samples showed >99.5% similarity to one another. INSV was previously reported to affect other crops in Mexico, including tomatillo (Physalis ixocarpa) and pepper (Capsicum spp.) (González-Pacheco and Silva-Rosales, 2013), while TSWV has been reported to infect lettuce (Moreno et al., 2016). To our knowledge, this is the first report of INSV infecting lettuce in Mexico and was the dominant orthotospovirus in lettuce samples that were tested. INSV should be closely monitored throughout central Mexico, where majority of lettuce production occurs. Additional studies are warranted to identify the thrips vector species that are present, and to understand the role of crop and non-crop hosts in the epidemiology of INSV throughout the region.

An update of the Couple Adaptation to Traumatic Stress Model: Systematic research synthesis of the association between secondary trauma survivor functioning and couple functioning.

Systemic theories addressing posttraumatic stress disorder (PTSD) in couples postulate associations between primary trauma survivor functioning, secondary trauma survivor functioning, and couple functioning. However, there is a lack of examination of the association between secondary trauma survivor functioning and couple functioning, which has clinical implications. Objectives of this study include informing clinicians of the evidence base for these associations and providing a synthesized review of research on PTSD in couples to inform future research. A systematic research synthesis screening 150 articles from three databases resulted in the inclusion of 15 quantitative articles to examine the quality of the available research addressing the association between secondary trauma survivor functioning and couple functioning. Correlation matrices in all studies and other partial evidence supported the current theory positing the relevance of secondary traumatic stress in interpersonal functioning for couples. Discussion includes the need for increased quality and diversity of systemic trauma research and treatment for couples.

An experimental system for detection and localization of hemorrhage using ultra-wideband microwaves with deep learning.

Stroke is a leading cause of mortality and disability. Emergent diagnosis and intervention are critical, and predicated upon initial brain imaging; however, existing clinical imaging modalities are generally costly, immobile, and demand highly specialized operation and interpretation. Low-energy microwaves have been explored as a low-cost, small form factor, fast, and safe probe for tissue dielectric properties measurements, with both imaging and diagnostic potential. Nevertheless, challenges inherent to microwave reconstruction have impeded progress, hence conduction of microwave imaging remains an elusive scientific aim. Herein, we introduce a dedicated experimental framework comprising a robotic navigation system to translate blood-mimicking phantoms within a human head model. An 8-element ultra-wideband array of modified antipodal Vivaldi antennas was developed and driven by a two-port vector network analyzer spanning 0.6-9.0 GHz at an operating power of 1 mW. Complex scattering parameters were measured, and dielectric signatures of hemorrhage were learned using a dedicated deep neural network for prediction of hemorrhage classes and localization. An overall sensitivity and specificity for detection >0.99 was observed, with Rayleigh mean localization error of 1.65 mm. The study establishes the feasibility of a robust experimental model and deep learning solution for ultra-wideband microwave stroke detection.

Particle Beam Radiobiology Status and Challenges: A PTCOG Radiobiology Subcommittee Report.

Particle therapy (PT) represents a significant advancement in cancer treatment, precisely targeting tumor cells while sparing surrounding healthy tissues thanks to the unique depth-dose profiles of the charged particles. Furthermore, their linear energy transfer and relative biological effectiveness enhance their capability to treat radioresistant tumors, including hypoxic ones. Over the years, extensive research has paved the way for PT's clinical application, and current efforts aim to refine its efficacy and precision, minimizing the toxicities. In this regard, radiobiology research is evolving toward integrating biotechnology to advance drug discovery and radiation therapy optimization. This shift from basic radiobiology to understanding the molecular mechanisms of PT aims to expand the therapeutic window through innovative dose delivery regimens and combined therapy approaches. This review, written by over 30 contributors from various countries, provides a comprehensive look at key research areas and new developments in PT radiobiology, emphasizing the innovations and techniques transforming the field, ranging from the radiobiology of new irradiation modalities to multimodal radiation therapy and modeling efforts. We highlight both advancements and knowledge gaps, with the aim of improving the understanding and application of PT in oncology.

DeepEMC-T2 mapping: Deep learning-enabled T2 mapping based on echo modulation curve modeling.

PURPOSE: Echo modulation curve (EMC) modeling enables accurate quantification of T2 relaxation times in multi-echo spin-echo (MESE) imaging. The standard EMC-T2 mapping framework, however, requires sufficient echoes and cumbersome pixel-wise dictionary-matching steps. This work proposes a deep learning version of EMC-T2 mapping, called DeepEMC-T2 mapping, to efficiently estimate accurate T2 maps from fewer echoes. METHODS: DeepEMC-T2 mapping was developed using a modified U-Net to estimate both T2 and proton density (PD) maps directly from MESE images. The network implements several new features to improve the accuracy of T2/PD estimation. A total of 67 MESE datasets acquired in axial orientation were used for network training and evaluation. An additional 57 datasets acquired in coronal orientation with different scan parameters were used to evaluate the generalizability of the framework. The performance of DeepEMC-T2 mapping was evaluated in seven experiments. RESULTS: Compared to the reference, DeepEMC-T2 mapping achieved T2 estimation errors from 1% to 11% and PD estimation errors from 0.4% to 1.5% with ten/seven/five/three echoes, which are more accurate than standard EMC-T2 mapping. By incorporating datasets acquired with different scan parameters and orientations for joint training, DeepEMC-T2 exhibits robust generalizability across varying imaging protocols. Increasing the echo spacing and including longer echoes improve the accuracy of parameter estimation. The new features proposed in DeepEMC-T2 mapping all enabled more accurate T2 estimation. CONCLUSIONS: DeepEMC-T2 mapping enables simplified, efficient, and accurate T2 quantification directly from MESE images without dictionary matching. Accurate T2 estimation from fewer echoes allows for increased volumetric coverage and/or higher slice resolution without prolonging total scan times.

Challenges and considerations for antifungal prophylaxis in children with acute myeloid leukemia.

INTRODUCTION: Children receiving treatment for acute myeloid leukemia (AML) are at high risk of invasive fungal disease (IFD). Evidence from pediatric studies support the efficacy of antifungal prophylaxis in reducing the burden of IFD in children receiving therapy for AML, yet existing antifungal agents have specific limitations and comparative data to inform the optimal prophylactic approach are lacking. AREAS COVERED: This review summarizes the epidemiology of invasive fungal disease (IFD) and current antifungal prophylaxis recommendations for children with acute myeloid leukemia (AML). Challenges with currently available antifungal agents and considerations related to the changing landscape of AML therapy are reviewed. A keyword search was conducted to identify pediatric studies regarding IFD and antifungal prophylaxis in children with AML up to December 2023. EXPERT OPINION: Children undergoing treatment for AML are recommended to receive antifungal prophylaxis to reduce risk of IFD, with tolerability, pharmacokinetics, feasibility of administration, and drug interactions all factors that require consideration in this context. With increased use of novel targeted agents for AML therapy, together with the development of new antifungal agents, data from well-designed clinical studies to optimize prophylactic approaches will be essential to limit the burden of IFD in this vulnerable cohort.

Naloxone and Patient Outcomes in Out-of-Hospital Cardiac Arrests in California.

Importance: The incidence of opioid-associated out-of-hospital cardiac arrest (OA-OHCA) has grown from less than 1% of OHCA in 2000 to between 7% and 14% of OHCA in recent years; American Heart Association (AHA) protocols suggest that emergency medical service (EMS) clinicians consider naloxone in OA-OHCA. However, it is unknown whether naloxone improves survival in these patients or in patients with undifferentiated OHCA. Objective: To evaluate the association of naloxone with clinical outcomes in patients with undifferentiated OHCA. Design, Setting, and Participants: Retrospective cohort study of EMS-treated patients aged 18 or older who received EMS treatment for nontraumatic OHCA in 3 Northern California counties between 2015 and 2023. Data were analyzed using propensity score-based models from February to April 2024. Exposure: EMS administration of naloxone. Main Outcomes and Measures: The primary outcome was survival to hospital discharge; the secondary outcome was sustained return of spontaneous circulation (ROSC). Covariates included patient and cardiac arrest characteristics (eg, age, sex, nonshockable rhythm, any comorbidity, unwitnessed arrest, and EMS agency) and EMS clinician determination of OHCA cause as presumed drug-related. Results: Among 8195 patients (median [IQR] age, 65 [51-78] years; 5540 male [67.6%]; 1304 Asian, Native Hawaiian, or Pacific Islander [15.9%]; 1119 Black [13.7%]; 2538 White [31.0%]) with OHCA treated by 5 EMS agencies from 2015 to 2023, 715 (8.7%) were believed by treating clinicians to have drug-related OHCA. Naloxone was administered to 1165 patients (14.2%) and was associated with increased ROSC using both nearest neighbor propensity matching (absolute risk difference [ARD], 15.2%; 95% CI, 9.9%-20.6%) and inverse propensity-weighted regression adjustment (ARD, 11.8%; 95% CI, 7.3%-16.4%). Naloxone was also associated with increased survival to hospital discharge using both nearest neighbor propensity matching (ARD, 6.2%; 95% CI, 2.3%-10.0%) and inverse propensity-weighted regression adjustment (ARD, 3.9%; 95% CI, 1.1%-6.7%). The number needed to treat with naloxone was 9 for ROSC and 26 for survival to hospital discharge. In a regression model that assessed effect modification between naloxone and presumed drug-related OHCA, naloxone was associated with improved survival to hospital discharge in both the presumed drug-related OHCA (odds ratio [OR], 2.48; 95% CI, 1.34-4.58) and non-drug-related OHCA groups (OR, 1.35; 95% CI, 1.04-1.77). Conclusions and Relevance: In this retrospective cohort study, naloxone administration as part of EMS management of OHCA was associated with increased rates of ROSC and increased survival to hospital discharge when evaluated using propensity score-based models. Given the lack of clinical practice data on the efficacy of naloxone in OA-OHCA and OHCA in general, these findings support further evaluation of naloxone as part of cardiac arrest care.

Durability of Aortic Homografts in Pulmonary Atresia and Major Aortopulmonary Collateral Arteries.

Objectives: It is well-known that right ventricle-to-pulmonary artery homograft conduit durability is worse for smaller conduits and smaller/younger patients. However, there is limited literature on age and conduit-size specific outcomes, or on the role of conduit oversizing. Methods: Patients diagnosed with tetralogy of Fallot and major aortopulmonary collateral arteries undergoing right ventricular outflow tract (RVOT) reconstruction with a valved aortic homograft conduit from November 2001 through March 2023, at our institution were included. Conduits were grouped and evaluated by diameter, diameter Z-score, and patient age at implant. The primary time-related outcome was freedom from RVOT reintervention. Factors associated with freedom from time-related outcomes were assessed with univariable Cox regression analysis. Results: A total of 863 RVOT conduits were implanted in 722 patients. On multivariable analysis, younger age, male sex, Alagille syndrome, smaller diameter of the conduit, and smaller Z-score were associated with shorter freedom from reintervention. Among patients with smaller diameter conduits, larger Z-scores were associated with longer freedom from conduit reintervention (P < .001). Transcatheter interventions were commonly used to extend conduit lifespan across ages and conduit sizes. Conclusions: Larger conduit diameter, older age, and higher conduit Z-score were associated with longer freedom from reintervention in patients undergoing RVOT reconstruction in this cohort. Oversizing of conduits, even beyond a Z-score of 4, is generally appropriate.

Targeted Protein Localization by Covalent 14-3-3 Recruitment.

14-3-3 proteins have a unique ability to bind and sequester a multitude of diverse phosphorylated signaling proteins and transcription factors. Many previous studies have shown that interactions of 14-3-3 with specific phosphorylated substrate proteins can be enhanced through small-molecule natural products or fully synthetic molecular glue interactions. However, enhancing 14-3-3 interactions with both therapeutically intractable transcription factor substrates and potential neo-substrates to sequester and inhibit their function remains elusive. One of the 14-3-3 proteins, 14-3-3σ or SFN, has cysteine C38 at the substrate-binding interface, near the sites where previous 14-3-3 molecular glues have been found to bind. In this study, we screen a fully synthetic cysteine-reactive covalent ligand library to identify molecular glues that enhance the interaction of 14-3-3σ with not only druggable transcription factors such as estrogen receptor (ERα) but also challenging oncogenic transcription factors such as YAP and TAZ, which are part of the Hippo transducer pathway. We identify a hit EN171 that covalently targets both C38 and C96 on 14-3-3 to enhance 14-3-3 interactions with ERα, YAP, and TAZ, leading to impaired estrogen receptor and Hippo pathway transcriptional activity. We further demonstrate that EN171 could not only be used as a molecular glue to enhance native protein interactions but could also be used as a covalent 14-3-3 recruiter in heterobifunctional molecules to sequester nuclear neo-substrates such as BRD4 and BLC6 into the cytosol. Overall, our study reveals a covalent ligand that acts as a novel 14-3-3 molecular glue for challenging transcription factors such as YAP and TAZ and demonstrates that these glues can be potentially utilized in heterobifunctional molecules to sequester nuclear neo-substrates out of the nucleus and into the cytosol to enable targeted protein localization.

Dispersion-free inertial focusing (DIF) for high-yield polydisperse micro-particle filtration and analysis.

Inertial focusing excels at the precise spatial ordering and separation of microparticles by size within fluid flows. However, this advantage, resulting from its inherent size-dependent dispersion, could turn into a drawback that challenges applications requiring consistent and uniform positioning of polydisperse particles, such as microfiltration and flow cytometry. To overcome this fundamental challenge, we introduce Dispersion-Free Inertial Focusing (DIF). This new method minimizes particle size-dependent dispersion while maintaining the high throughput and precision of standard inertial focusing, even in a highly polydisperse scenario. We demonstrate a rule-of-thumb principle to reinvent an inertial focusing system and achieve an efficient focusing of particles ranging from 6 to 30 µm in diameter onto a single plane with less than 3 µm variance and over 95% focusing efficiency at highly scalable throughput (2.4-30 mL h-1) - a stark contrast to existing technologies that struggle with polydispersity. We demonstrated that DIF could be applied in a broad range of applications, particularly enabling high-yield continuous microparticle filtration and large-scale high-resolution single-cell morphological analysis of heterogeneous cell populations. This new technique is also readily compatible with the existing inertial microfluidic design and thus could unleash more diverse systems and applications.

Herpes simplex virus in infancy: Evaluation of national surveillance case capture.

AIM: As herpes simplex virus (HSV) in infancy is not a mandatory notifiable condition in Australia, completeness of ascertainment by the Australian Paediatric Surveillance Unit (APSU) has been difficult to evaluate to date. We evaluated case capture in Queensland (QLD) and Western Australia (WA) using statewide laboratory and clinical data and complementary surveillance data collected via the APSU. METHODS: HSV polymerase chain reaction positive results in infants (0-3 months) from 2007 to 2017 were obtained from statewide public pathology providers in QLD and WA. Clinical data were extracted from patient records and compared to APSU reported cases. RESULTS: A total of 94 cases of HSV disease in infancy (70 QLD; 24 WA) were identified from laboratory data sets, compared to 36 cases (26 QLD; 10 WA) reported to the APSU. In total there was 102 unique cases identified; 28 cases were common to both data sets (seven skin eye mouth (SEM) disease, 13 central nervous system (CNS) disease and eight disseminated disease). Active surveillance captured 35% (36/102) of cases overall including 74% (14/19) of CNS, 71% (10/14) of disseminated and 17% (12/69) of SEM disease cases, respectively. Surveillance reported cases had a higher case-fatality rate compared to those not reported (14% vs. 3%, P = 0.038). Neurological sequelae at discharge were comparable between the groups. CONCLUSION: Active surveillance captures one third of hospitalised HSV cases in QLD and WA, including the majority with severe disease. However, morbidity and mortality remain high. Future studies on HSV will rely on observational studies. Enhanced case ascertainment through combined laboratory and surveillance data is essential for better understanding and improving outcomes.

Developing and validating a clinical risk score to predict losses in the PISCIS cohort of people with HIV.

BACKGROUND: People lost to follow-up (LTFU) from HIV care have an increased risk of worse health. The objective of this study is to create and validate a risk score to predict LTFU among PLWH in Catalonia and the Balearic Islands. METHODS: 6661 PLWH were included. LTFU were those without contact with HIV care for 12 months or more. Logistic regression models were used to assess the role of independent factors on LTFU. The validation included a 10-fold iteration to predict the performance of the regression model and the Area under the ROC Curve (AUC). Regression coefficients were rounded and summed to construct the score. RESULTS: Determinants of LTFU included being younger than 34 years (OR: 1.80, CI, 1.44-2.23), not having been born in Spain (OR: 1.32, 1.11-1.58), men who inject drugs (OR: 2.10, 1.38-3.19), having a detectable viral load (OR: 3.14, 2.47-3.99), and ≤2.5 years since HIV diagnosis (OR: 3.84, 3.10-4.75). The validation of determinants resulted in a mean AUC of 0.69 and the risk-score revealed that 28.8% had a medium and 3.4% a high risk of LTFU respectively. CONCLUSIONS: Findings can be used to prevent LTFU in HIV care.