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Health equity is shaped by multiple factors intersecting with service delivery in community-based organizations (CBOs). Providers in under-resourced areas are often the first point of contact for families seeking child development, mental health, and behavioral support. However, system-level barriers hinder service delivery and access. This study explores provider perspectives to identify barriers and inform system-level changes that promote equity in child and family health. Using a narrative qualitative design, in-depth interviews were conducted with 21 health and mental health professionals from child- and family-serving CBOs. Guided by ecological and strengths-based frameworks, interviews examined provider insights on challenges, strengths, and supports affecting service delivery. Key themes emerged across macro (rights-based policies, racism/oppression), community (environmental impacts, social cohesion), organizational (secondary stress, system fragmentation, provider supports), and family levels (basic needs, parenting support, service access). Findings highlight the need for a multilevel approach that prioritizes rights-based policies, strengthens community cohesion, and improves system integration. Enhancing CBO capacity to address these determinants could advance equity-oriented service delivery and mitigate structural barriers that perpetuate health disparities.

There is limited knowledge about African-American women aged 85 years and older and their development of resilience. One way in which we can know more about this group is through retrospective studies of their experiences. Therefore, this retrospective study examined how Black American women, aged 85 years and older, residing in the Philadelphia metropolitan area perceived their development of resilience. Core themes that emerged from the author's analysis of the qualitative interviews were: familial factors, community factors, and individual factors. The findings suggest that the women in this study developed resilience in part as a result of their environment as well as their inherent characteristics. This study adds to the knowledge base in the areas of resilience and aging. Research in both areas has demonstrated the importance of family and support systems, but most research has focused on resilience at a fixed point in the life cycle rather than on its development. Exploring the development of resilience has the potential to help others either become resilient or to make the best of those characteristics that are said to enhance resilience.

Elagolix is a nonpeptide, oral gonadotropin-releasing hormone (GnRH) antagonist being developed for sex-hormone-dependent diseases in women. We evaluated the pharmacokinetics and pharmacodynamics of elagolix. This study was a randomized, double-blind, placebo-controlled, multiple-ascending dose study in 45 healthy premenopausal women at a research unit. Elagolix [150 mg once daily or 100, 200, 300, or 400 mg twice daily (BID)] or placebo was administered for 21 days. Main outcome measures were elagolix pharmacokinetics, suppression of gonadotropics [follicle-stimulating hormone (FSH), luteinizing hormone (LH)] and ovarian hormones [estradiol (E2), progesterone (P)], and adverse events. Elagolix was rapidly absorbed after oral dosing, reaching maximum concentrations at 1.0 to 1.5 hours, with a half-life of 4 to 6 hours. FSH, LH, and E2 were suppressed within hours of elagolix administration on day 1. Dose-dependent suppression of E2 was observed, with maximum suppression achieved with elagolix 200 mg BID. Dose-dependent suppression of FSH and LH was also observed, with maximal or near-maximal suppression achieved at 300 mg BID and 200 mg BID, respectively. At elagolix doses ≥100 mg BID, P concentrations remained at anovulatory levels throughout 21 days of dosing. The most frequently reported adverse events were headache and hot flush. Elagolix administration allows for modulation of gonadotropin and ovarian hormone concentrations, from partial suppression at lower doses to nearly full suppression at higher doses. The results of this study provide a rationale for elagolix dose selection for treatment of sex hormone-dependent diseases in women.

The great majority of globally circulating pathogens go undetected, undermining patient care and hindering outbreak preparedness and response. To enable routine surveillance and comprehensive diagnostic applications, there is a need for detection technologies that can scale to test many samples 1 , 2 – 3 while simultaneously testing for many pathogens 4 , 5 – 6 . Here, we develop Combinatorial Arrayed Reactions for Multiplexed Evaluation of Nucleic acids (CARMEN), a platform for scalable, multiplexed pathogen detection. In the CARMEN platform, nanolitre droplets containing CRISPR-based nucleic acid detection reagents 7 self-organize in a microwell array 8 to pair with droplets of amplified samples, testing each sample against each CRISPR RNA (crRNA) in replicate. The combination of CARMEN and Cas13 detection (CARMEN–Cas13) enables robust testing of more than 4,500 crRNA–target pairs on a single array. Using CARMEN–Cas13, we developed a multiplexed assay that simultaneously differentiates all 169 human-associated viruses with at least 10 published genome sequences and rapidly incorporated an additional crRNA to detect the causative agent of the 2020 COVID-19 pandemic. CARMEN–Cas13 further enables comprehensive subtyping of influenza A strains and multiplexed identification of dozens of HIV drug-resistance mutations. The intrinsic multiplexing and throughput capabilities of CARMEN make it practical to scale, as miniaturization decreases reagent cost per test by more than 300-fold. Scalable, highly multiplexed CRISPR-based nucleic acid detection shifts diagnostic and surveillance efforts from targeted testing of high-priority samples to comprehensive testing of large sample sets, greatly benefiting patients and public health 9 , 10 – 11 . CRISPR-based nucleic acid detection is used in a platform that can simultaneously detect 169 human-associated viruses in multiple samples, providing scalable, multiplexed pathogen detection aimed at routine surveillance for public health.

The parasitic filariae responsible for onchocerciasis and lymphatic filariasis are host to an endosymbiotic bacterium, Wolbachia, which is essential to the fertility and development of the parasites. We performed a Phase-I pharmacokinetic, safety and food-effect study on single and multiple ascending doses of flubentylosin (ABBV-4083), a macrolide antibacterial with activity against Wolbachia, intended to sterilize and eliminate the parasites. Seventy-eight healthy adults were exposed to flubentylosin; 36 were exposed to single ascending 40, 100, 200, 400 or 1000 mg doses; 12 received 1000 mg in the food-effect part; and 30 received multiple ascending daily doses of 100 mg for 7 days, 200 mg for 7 or 14 days, or 400 mg for 7 or 14 days. Twenty-two subjects received placebo. Maximum concentrations (Cmax) of flubentylosin were reached after 1-2 hours, with a half-life < 4 hours at doses ≤ 400 mg. Cmax and AUC increased in a more than dose-proportional manner, with similar exposure after multiple dose administration. The most frequently reported adverse events were nausea (8/78, 10%) and headache (6/78, 8%). Two subjects given a single dose of flubentylosin 1000 mg in the food-effect part experienced reversible asymptomatic ALT and AST elevations at Grade 2 or Grade 4, with no elevation in bilirubin, deemed related to study drug. The effect of food on exposure parameters was minimal. No treatment-related serious adverse events were reported. Flubentylosin 400 mg for 14 days was the maximum tolerated dose in this first-in-human, Phase-I study in healthy adults. Based on preclinical pharmacokinetic/pharmacodynamic modeling, flubentylosin 400 mg once daily for 7 or 14 days is expected to be an effective dose. A Phase-II, proof-of-concept study with flubentylosin using these regimens is currently ongoing in patients with onchocerciasis in Africa.

Onchocerciasis remains a debilitating neglected tropical disease. Due to the many challenges of current control methods, an effective vaccine against the causative agent Onchocerca volvulus is urgently needed. Mice and cynomolgus macaque non-human primates (NHPs) were immunized with a vaccine consisting of a fusion of two O. volvulus protein antigens, Ov-103 and Ov-RAL-2 (Ov-FUS-1), and three different adjuvants: Advax-CpG, alum, and AlT4. All vaccine formulations induced high antigen-specific IgG titers in both mice and NHPs. Challenging mice with O. volvulus L3 contained within subcutaneous diffusion chambers demonstrated that Ov-FUS-1/Advax-CpG-immunized animals developed protective immunity, durable for at least 11 weeks. Passive transfer of sera, collected at several time points, from both mice and NHPs immunized with Ov-FUS-1/Advax-CpG transferred protection to naïve mice. These results demonstrate that Ov-FUS-1 with the adjuvant Advax-CpG induces durable protective immunity against O. volvulus in mice and NHPs that is mediated by vaccine-induced humoral factors.

Disorganized intercellular junctions are critical for maintaining the integrity of solid epithelial tumors and prevent the infiltration of oncological therapies into the bulk of the malignancy. We have developed small, recombinant proteins which bind a critical junction protein, desmoglein 2, triggering the transient and specific opening of tumor tight junctions allowing for infiltration of the tumor with immune cells, oncolytic viruses, drugs, and other therapeutics. Our new molecule, JOC- x , is a promising candidate for a new class of tumor-targeting agents that accumulate both around and within tumors and remodel the tumor microenvironment. Native cysteines were removed from the parental protein, JO-4, followed by addition of a single cysteine to allow for convenient attachment of various payloads that can be targeted directly to the tumor. Our tumor-targeting protein exhibits high avidity, minimal aggregation, and is easily purified at good yields from E. coli . For proof of concept, we demonstrate effective conjugation to biotin as a model for flexible co-targeting, addition of metal ion chelators as models for imaging and radiotherapy, and linkage of the TLR3 agonist poly(I:C) as a model immune-oncologic agent. This second-generation cancer co-therapeutic protein is optimized for activity and primed for cGMP manufacture in preparation for upcoming clinical studies.

ObjectiveTo compare neurodevelopmental outcomes in linear growth-restricted (LGR) infants born <29 weeks with and without weight gain out of proportion to linear growth.Study designWe compared 2-year neurodevelopmental outcomes between infants with and without LGR and between LGR infants with and without weight gain out of proportion to linear growth. The outcomes were Bayley-III cognitive, motor, and language scores, cerebral palsy, Gross Motor Function Classification System (GMFCS) level ≥ 2, and neurodevelopmental impairment.ResultIn total, 1227 infants were analyzed. LGR infants were smaller and less mature at birth, had higher BMI, and had lower Bayley-III language scores (82.3 vs. 85.0, p < 0.05). Among infants with LGR, infants with high BMI had lower language scores compared with those with low-to-normal BMI (80.8 vs. 83.3, p < 0.05), and were more likely to have GMFCS level ≥2 and neurodevelopmental impairment.ConclusionAmong infants with LGR, weight gain out of proportion to linear growth was associated with poorer neurodevelopmental outcomes.

Onchocerciasis remains a debilitating neglected tropical disease. Due to the many challenges of current control methods, an effective vaccine against the causative agent Onchocerca volvulus is urgently needed. Mice and cynomolgus macaque non-human primates (NHPs) were immunized with a vaccine consisting of a fusion of two O. volvulus protein antigens, Ov-103 and Ov-RAL-2 (Ov-FUS-1), and three different adjuvants: Advax-CpG, alum, and AlT4. All vaccine formulations induced high antigen-specific IgG titers in both mice and NHPs. Challenging mice with O. volvulus L3 contained within subcutaneous diffusion chambers demonstrated that Ov-FUS-1/Advax-CpG-immunized animals developed protective immunity, durable for at least 11 weeks. Passive transfer of sera, collected at several time points, from both mice and NHPs immunized with Ov-FUS-1/Advax-CpG transferred protection to naïve mice. These results demonstrate that Ov-FUS-1 with the adjuvant Advax-CpG induces durable protective immunity against O. volvulus in mice and NHPs that is mediated by vaccine-induced humoral factors.

Local protein synthesis in axons and dendrites underpins synaptic plasticity. However, the composition of the protein synthesis machinery in distal neuronal processes and the mechanisms for its activity-driven deployment to local translation sites remain unclear. Here, we employed cryo-electron tomography, volume electron microscopy, and live-cell imaging to identify Ribosome-Associated Vesicles (RAVs) as a dynamic platform for moving ribosomes to distal processes. Stimulation via chemically-induced long-term potentiation causes RAV accumulation in distal sites to drive local translation. We also demonstrate activity-driven changes in RAV generation and dynamics , identifying tubular ER shaping proteins in RAV biogenesis. Together, our work identifies a mechanism for ribosomal delivery to distal sites in neurons to promote activity-dependent local translation.