Progress towards malaria elimination in the Greater Mekong Subregion: perspectives from the World Health Organization.

Malaria remains a global health challenge, disproportionately affecting vulnerable communities. Despite substantial progress, the emergence of anti-malarial drug resistance poses a constant threat. The Greater Mekong Subregion (GMS), which includes Cambodia, China's Yunnan province, Lao People's Democratic Republic, Myanmar, Thailand, and Viet Nam has been the epicentre for the emergence of resistance to successive generations of anti-malarial therapies. From the perspective of the World Health Organization (WHO), this article considers the collaborative efforts in the GMS, to contain Plasmodium falciparum artemisinin partial resistance and multi-drug resistance and to advance malaria elimination. The emergence of artemisinin partial resistance in the GMS necessitated urgent action and regional collaboration resulting in the Strategy for Malaria Elimination in the Greater Mekong Subregion (2015-2030), advocating for accelerated malaria elimination interventions tailored to country needs, co-ordinated and supported by the WHO Mekong malaria elimination programme. The strategy has delivered substantial reductions in malaria across all GMS countries, with a 77% reduction in malaria cases and a 97% reduction in malaria deaths across the GMS between 2012 and 2022. Notably, China was certified malaria-free by WHO in 2021. Countries' ownership and accountability have been pivotal, with each GMS country outlining its priorities in strategic and annual work plans. The development of strong networks for anti-malarial drug resistance surveillance and epidemiological surveillance was essential. Harmonization of policies and guidelines enhanced collaboration, ensuring that activities were driven by evidence. Challenges persist, particularly in Myanmar, where security concerns have limited recent progress, though an intensification and acceleration plan aims to regain momentum. Barriers to implementation can slow progress and continuing innovation is needed. Accessing mobile and migrant populations is key to addressing remaining transmission foci, requiring effective cross-border collaboration. In conclusion, the GMS has made significant progress towards malaria elimination, particularly in the east where several countries are close to P. falciparum elimination. New and persisting challenges require sustained efforts and continued close collaboration. The GMS countries have repeatedly risen to every obstacle presented, and now is the time to re-double efforts and achieve the 2030 goal of malaria elimination for the region.

Formation of Trideuteromethylated Artifacts of Pyrrole-Containing Natural Products.

Pyrrole-containing natural products form a large group of structurally diverse compounds that occur in both terrestrial and marine organisms. In the present study the formation of trideuteromethylated artifacts of pyrrole-containing natural products was investigated, focusing on the discorhabdins. Three deuterated discorhabdins, 1, 3, and 5, were identified to be isolation procedure artifacts caused by the presence of DMSO-d6 during NMR sample preparation and handling. Three additional semisynthetic derivatives, 7-9, were made during the investigation of the mechanism of formation, which was shown to be driven by trideuteromethyl radicals in the presence of water, methanol, TFA, and traces of iron in the deuterated solvent. Generation of trideuteromethylated artifacts was also confirmed for other classes of pyrrole-containing metabolites, namely, makaluvamines, tambjamines, and dibromotryptamines, which had also been dissolved in DMSO-d6 during the structure elucidation process. Semisynthetic discorhabdins were assessed for antiproliferative activity against a panel of human tumor cell lines, and 14-trideuteromethyldiscorhabdin L (3) averaged low micromolar potency.

Prospective, open-label, multicenter clinical study to assess the performance of a new donation system for the collection of source plasma.

BACKGROUND: Safe, efficient, and reliable innovations among donation systems are needed to meet the growing global demand for source plasma. This study assessed the ability of a new donation system to collect appropriate product weights based on the US Food and Drug Administration nomogram for source plasma collections. Procedure duration and safety endpoints were also collected. STUDY DESIGN AND METHODS: The Rika Plasma Donation System (Terumo BCT, Inc., Lakewood, CO) was evaluated in a prospective, open-label, multicenter study. Healthy adults meeting FDA and Plasma Protein Therapeutics Association requirements for source plasma donor eligibility were consented and enrolled in the study resulting in 124 evaluable products. RESULTS: The target product collection weights (ie, including plasma and anticoagulant) by participant weight category were: 705 g (110-149 lbs), 845 g (150-174 lbs), and 900 g (≥175 lbs). The mean reported product collection weights by participant weight category were 705.0 ± 0.00, 845.0 ± 0.20, and 899.9 ± 0.31 g, respectively. The mean overall procedure time was 31.5 ± 5.41 minutes. The mean procedure times by participant weight category were 25.6 ± 3.13, 30.5 ± 4.45, and 33.7 ± 4.80 minutes, respectively. Procedure-emergent adverse events (PEAEs) occurred in five participants. All PEAEs were consistent with known risks for apheresis donation, and none were related to the donation system. CONCLUSIONS: The new donation system collected the target product collection weight in 100% of evaluable products. The mean procedure collection time was 31.5 minutes. The system is a new efficient platform that consistently collects the appropriate weight of the source plasma.

Contact: William S. Burroughs's philosophy of love.

The present psychobiography took up the three main psychoanalytic conceptions of love to illuminate the psychological development of famed experimental writer William Seward Burroughs (1914-1997). The study found evidence of all three concepts of love in the subject's life strategies: (1) Love as cathexis was present in Burroughs' fascination with centipedes and other vermin that appeared in his dreams and which symbolised, in part, his terror over early childhood traumas as well as his concomitant struggle to integrate sex with intimacy. (2) Love as eroto-philiac fusion was observed in Burroughs' unstable and even exploitative relationships with others. This tendency was most salient in Burroughs' abortive attempts to seduce straight men, as well as in his failed efforts to be a traditional husband and father. (3) Reparative love became the subject's primary mode of interaction late in life. The study showed that, in his declining years, Burroughs was able to overcome partially the maladaptive strategies of his early life through his numerous pet cats, upon whom he projected aspects of his past romantic partners and friends.

Remote Evidence-Based Health Promotion Programs During COVID: A National Evaluation of Reach and Implementation for Older Adult Health Equity.

INTRODUCTION.: Evidence-based health promotion programs (EBPs) support older adults where they live, work, pray, play, and age. COVID-19 placed a disproportionate burden on this population, especially those with chronic conditions. In-person EBPs shifted to remote delivery via video-conferencing, phone, and mail during the pandemic, creating opportunities and challenges for older adult health equity. METHOD.: In 2021-2022, we conducted a process evaluation of remote EBPs by purposively sampling diverse U.S. organizations and older adults (people of color, rural, and/or with disabilities). The Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) + Equity framework was used to understand program reach and implementation, including FRAME to describe adaptations for remote delivery. Analyses include descriptive statistics and thematic analysis of participant and provider surveys and interviews, and joint display tables to compare learnings. RESULTS.: Findings from 31 EBPs through 198 managers/leaders and 107 organizations suggest remote delivery increases EBP reach by improving access for older adults who are underserved. For programs requiring new software or hardware, challenges remain reaching those with limited access to-or comfort using-technology. Adaptations were to context (e.g., shorter, smaller classes with longer duration) and for equity (e.g., phone formats, autogenerated captioning); content was unchanged except where safety was concerned. Implementation is facilitated by remote delivery guidelines, distance training, and technology support; and hindered by additional time, staffing, and resources for engagement and delivery. CONCLUSIONS.: Remote EBP delivery is promising for improving equitable access to quality health promotion. Future policies and practices must support technology access and usability for all older adults.

Digitally enabled hemovigilance allows real time response to transfusion reactions.

BACKGROUND: Transfusion carries a risk of transfusion reaction that is often underdiagnosed due to reliance on passive reporting. The study investigated the utility of digital methods to identify potential transfusion reactions, thus allowing real-time intervention for affected patients. METHOD: The hemovigilance unit monitored 3856 patients receiving 43,515 transfusions under the hemovigilance program. Retrospective comparison data included 298,498 transfusions. Transfusion medicine physicians designed and validated algorithms in the electronic health record that analyze discrete data, such as vital sign changes, to assign a risk score during each transfusion. Dedicated hemovigilance nurses remotely monitor all patients and perform real-time chart reviews prioritized by risk score. When a reaction is suspected, a hemovigilance trained licensed clinician responds to manage the patient and ensure data collection. Board-certified transfusion medicine physicians reviewed data and classified transfusion reactions under various categories according to the Centers for Disease Control hemovigilance definitions. RESULTS: Transfusion medicine physicians diagnosed 564 transfusion reactions (1.3% of transfusions)-a 524% increase compared to the previous passive reporting. The rapid response provider reached the bedside on average at 12.4 min demonstrating logistic feasibility. While febrile reactions were most diagnosed, recognition of transfusion-associated circulatory overload demonstrated the greatest relative increase. Auditing and education programs further enhanced transfusion reaction awareness. DISCUSSION: The model of digitally-enabled expert real-time review of clinical data that prompts rapid response improved recognition of transfusion reactions. This approach could be applied to other patient deterioration events such as early identification of sepsis.

Recifin A, Initial Example of the Tyr-Lock Peptide Structural Family, Is a Selective Allosteric Inhibitor of Tyrosyl-DNA Phosphodiesterase I.

Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a molecular target for the sensitization of cancer cells to the FDA-approved topoisomerase inhibitors topotecan and irinotecan. High-throughput screening of natural product extract and fraction libraries for inhibitors of TDP1 activity resulted in the discovery of a new class of knotted cyclic peptides from the marine sponge Axinella sp. Bioassay-guided fractionation of the source extract resulted in the isolation of the active component which was determined to be an unprecedented 42-residue cysteine-rich peptide named recifin A. The native NMR structure revealed a novel fold comprising a four strand antiparallel ß-sheet and two helical turns stabilized by a complex disulfide bond network that creates an embedded ring around one of the strands. The resulting structure, which we have termed the Tyr-lock peptide family, is stabilized by a tyrosine residue locked into three-dimensional space. Recifin A inhibited the cleavage of phosphodiester bonds by TDP1 in a FRET assay with an IC50 of 190 nM. Enzyme kinetics studies revealed that recifin A can specifically modulate the enzymatic activity of full-length TDP1 while not affecting the activity of a truncated catalytic domain of TDP1 lacking the N-terminal regulatory domain (Δ1-147), suggesting an allosteric binding site for recifin A on the regulatory domain of TDP1. Recifin A represents both the first of a unique structural class of knotted disulfide-rich peptides and defines a previously unseen mechanism of TDP1 inhibition that could be productively exploited for potential anticancer applications.

Multiphase Assembly of Small Molecule Microcrystalline Peptide Hydrogel Allows Immunomodulatory Combination Therapy for Long-Term Heart Transplant Survival.

Combination therapies that target multiple pathways involved in immune rejection of transplants hold promise for patients in need of restorative surgery. Herein, a noninteracting multiphase molecular assembly approach is developed to crystallize tofacitinib, a potent JAK1/3 inhibitor, within a shear-thinning self-assembled fibrillar peptide hydrogel network. The resulting microcrystalline tofacitinib hydrogel (MTH) can be syringe-injected directly to the grafting site during surgery to locally deliver the small molecule. The rate of drug delivered from MTH is largely controlled by the dissolution of the encapsulated microcrystals. A single application of MTH, in combination with systemically delivered CTLA4-Ig, a co-stimulation inhibitor, affords significant graft survival in mice receiving heterotopic heart transplants. Locoregional studies indicate that the local delivery of tofacitinib at the graft site enabled by MTH is required for the observed enhanced graft survival.

Strengthening policy coding methodologies to improve COVID-19 disease modeling and policy responses: a proposed coding framework and recommendations.

BACKGROUND: In recent months, multiple efforts have sought to characterize COVID-19 social distancing policy responses. These efforts have used various coding frameworks, but many have relied on coding methodologies that may not adequately describe the gradient in social distancing policies as states "re-open." METHODS: We developed a COVID-19 social distancing intensity framework that is sufficiently specific and sensitive to capture this gradient. Based on a review of policies from a 12 U.S. state sample, we developed a social distancing intensity framework consisting of 16 domains and intensity scales of 0-5 for each domain. RESULTS: We found that the states with the highest average daily intensity from our sample were Pennsylvania, Washington, Colorado, California, and New Jersey, with Georgia, Florida, Massachusetts, and Texas having the lowest. While some domains (such as restaurants and movie theaters) showed bimodal policy intensity distributions compatible with binary (yes/no) coding, others (such as childcare and religious gatherings) showed broader variability that would be missed without more granular coding. CONCLUSION: This detailed intensity framework reveals the granularity and nuance between social distancing policy responses. Developing standardized approaches for constructing policy taxonomies and coding processes may facilitate more rigorous policy analysis and improve disease modeling efforts.

Outline for a future psychiatry: the transcendent meaning model (TMM).

The now-dominant medical model of psychiatry has recently been challenged by the post-psychiatry movement. However, the former discounts the agential or subjective aspect of the human being; the latter misses the axiological aspect. A new model is proposed-the Transcendent Meaning Model (TMM)-that nests the individual person within the social (the interperson), and the social within the transcendent or ideological. The study concludes that TMM, with its integration of the personal, the social and the religious-ideological with the material, is a viable blueprint for a future psychiatry that can address some of the current model's vulnerabilities.