Effect of multi-level social risk factors on developmental trajectories of sexual risk behaviors among Bahamian middle-to-late adolescents.

Background: Few studies have examined how multi-level social factors interact and affect developmental patterns of sexual risk among middle-to-late adolescents who are at risk of experiencing sexual risk behaviors. We examined developmental trajectories of sexual risk behaviors of boys and girls in middle-to-late adolescence and the effects of exposure to three social risk factors (poor parental monitoring, peer risk, and neighborhood risk). Methods: We followed 2,332 Bahamian adolescents every six months from Grades 10-12. We used group-based trajectory modeling to identify distinct trajectories of sexual risk behaviors for boys and girls. Results: We identified three trajectories each for boys and girls. Peer risk and neighborhood risk predicted a high sexual-risk trajectory for boys, and peer risk (alone or combined with other risk factors) had the greatest impact on the membership of moderate-to-high-risk trajectory for girls. Parental monitoring had a relatively small effect on adolescents' sexual risk behavior. Conclusion: Our results underscore the importance of early identification of adolescents with sexual risk behavior and development of targeted prevention interventions to improve adolescent health outcomes.

Fabrication of Poly Lactic-co-Glycolic Acid Microneedles for Sustained Delivery of Lipophilic Peptide-Carfilzomib.

Transdermal drug delivery (TDD) is an attractive route of administration, providing several advantages, especially over oral and parenteral routes. However, TDD is significantly restricted due to the barrier imposed by the uppermost layer of the skin, the stratum corneum (SC). Microneedles is a physical enhancement technique that efficiently pierces the SC and facilitates the delivery of both lipophilic and hydrophilic molecules. Dissolving microneedles is a commonly used type that is fabricated utilizing various biodegradable and biocompatible polymers, such as polylactic acid, polyglycolic acid, or poly(lactide-co-glycolide) (PLGA). Such polymers also promote the prolonged release of the drug due to the slow degradation of the polymer matrix following its insertion. We selected carfilzomib, a small therapeutic peptide (MW: 719.924 g/mol, log P 4.19), as a model drug to fabricate a microneedle-based sustained delivery system. This study is a proof-of-concept investigation in which we fabricated PLGA microneedles using four types of PLGA (50-2A, 50-5A, 75-5A, and 50-7P) to evaluate the feasibility of long-acting transdermal delivery of carfilzomib. Micromolding technique was used to fabricate the PLGA microneedles and characterization tests, including Fourier transform infrared spectroscopy, insertion capability using the skin simulant Parafilm model, histological evaluation, scanning electron microscopy, and confocal microscopy were conducted. In vitro release and permeation testing were conducted in vertical Franz diffusion cells. N-methyl pyrrolidone was utilized as the organic solvent and microneedles were solidified in controlled conditions, which led to good mechanical strength. Both in vitro release and permeation testing showed sustained profiles of carfilzomib over 7 days. The release and permeation were significantly influenced by the molecular weight of PLGA and the lipophilic properties of carfilzomib.

Ocular biometric parameters in South-Indian children with myopia - A hospital-based retrospective descriptive analysis.

AIM: This study aims to profile the ocular biometric parameters in a large group of children of South-Indian ethnicity who visited our outpatient children's department and were diagnosed with myopia. METHODS: Children <15 years old diagnosed with myopia (Jan 2022-Oct 2023) and who had ocular biometry readings recorded were included. Their demographics, axial length (AL), anterior chamber depth (ACD), spherical equivalent (SE), corneal radius of curvature (CR), and AL/CR ratio were analyzed. RESULTS: The study included 3728 myopic children; the mean age was 11.85 (4-15) years, and 52.8% were girls. Mean SE was -3.98 D. The mean (SD) AL, ACD, CR, and AL/CR ratio were 24.64 (1.32), 3.73 (0.40), 7.61 (0.27), and 3.24 (0.16), respectively. Female gender was associated with shorter AL, ACD, CR, and AL/CR ratios (P < 0.001) across all age groups. There was a significant increase in ACD with age in both sexes (P < 0.001). A 1-unit (mm) increase in AL was associated with an SE increase of -1.65 D (CL: -1.70 to -1.60). AL/CR ratio could explain 71% of the total variance in SE (P < 0.001). SE showed a mild correlation with age (rho = 0.14, P < 0.001) and ACD (rho = -0.03, P = 0.041) and a stronger correlation with AL (rho = -0.68, P < 0.001) and AL/CR (rho = -0.83, P < 0.001). CONCLUSION: In this hospital-based study, AL and AL/CR ratios strongly correlate with SE, and the AL/CR better explains the total variance in SE than AL alone in children with myopia.

Evaluation and Management of Kidney Dysfunction in Advanced Heart Failure: A Scientific Statement From the American Heart Association.

Early identification of kidney dysfunction in patients with advanced heart failure is crucial for timely interventions. In addition to elevations in serum creatinine, kidney dysfunction encompasses inadequate maintenance of sodium and volume homeostasis, retention of uremic solutes, and disrupted endocrine functions. Hemodynamic derangements and maladaptive neurohormonal upregulations contribute to fluctuations in kidney indices and electrolytes that may recover with guideline-directed medical therapy. Quantifying the extent of underlying irreversible intrinsic kidney disease is crucial in predicting whether optimization of congestion and guideline-directed medical therapy can stabilize kidney function. This scientific statement focuses on clinical management of patients experiencing kidney dysfunction through the trajectory of advanced heart failure, with specific focus on (1) the conceptual framework for appropriate evaluation of kidney dysfunction within the context of clinical trajectories in advanced heart failure, including in the consideration of advanced heart failure therapies; (2) preoperative, perioperative, and postoperative approaches to evaluation and management of kidney disease for advanced surgical therapies (durable left ventricular assist device/heart transplantation) and kidney replacement therapies; and (3) the key concepts in palliative care and decision-making processes unique to individuals with concomitant advanced heart failure and kidney disease.

Mapping cellular interactions from spatially resolved transcriptomics data.

Cell-cell communication (CCC) is essential to how life forms and functions. However, accurate, high-throughput mapping of how expression of all genes in one cell affects expression of all genes in another cell is made possible only recently through the introduction of spatially resolved transcriptomics (SRT) technologies, especially those that achieve single-cell resolution. Nevertheless, substantial challenges remain to analyze such highly complex data properly. Here, we introduce a multiple-instance learning framework, Spacia, to detect CCCs from data generated by SRTs, by uniquely exploiting their spatial modality. We highlight Spacia's power to overcome fundamental limitations of popular analytical tools for inference of CCCs, including losing single-cell resolution, limited to ligand-receptor relationships and prior interaction databases, high false positive rates and, most importantly, the lack of consideration of the multiple-sender-to-one-receiver paradigm. We evaluated the fitness of Spacia for three commercialized single-cell resolution SRT technologies: MERSCOPE/Vizgen, CosMx/NanoString and Xenium/10x. Overall, Spacia represents a notable step in advancing quantitative theories of cellular communications.

Advancing EDGE Zones to identify spatial conservation priorities of tetrapod evolutionary history.

The biodiversity crisis is pruning the Tree of Life in a way that threatens billions of years of evolutionary history and there is a need to understand where the greatest losses are predicted to occur. We therefore present threatened evolutionary history mapped for all tetrapod groups and describe patterns of Evolutionarily Distinct and Globally Endangered (EDGE) species. Using a complementarity procedure with uncertainty incorporated for 33,628 species, we identify 25 priority tetrapod EDGE Zones, which are insufficiently protected and disproportionately exposed to high human pressure. Tetrapod EDGE Zones are spread over five continents, 33 countries, and 117 ecoregions. Together, they occupy 0.723% of the world's surface but harbour one-third of the world's threatened evolutionary history and EDGE tetrapod species, half of which is endemic. These EDGE Zones highlight areas of immediate concern for researchers, practitioners, policymakers, and communicators looking to safeguard the tetrapod Tree of Life.

First Results of the Primary Outcome of a Phase II Prospective Clinical Trial to Assess the Feasibility of Preoperative Radiation Boost in Breast Cancer Patients.

INTRODUCTION: A radiation (RT) boost to the tumor bed is an important component of breast-conserving therapy (BCT) in early breast cancer (BC). This prospective phase II study assessed the feasibility of delivering the RT boost pre-operatively. We hypothesize wound complication rates to be comparable to post-operative RT and the target boost volume to be smaller than standard post-operative RT. METHODS: This prospective phase II trial accrued 55 patients with clinically node negative BC eligible for BCT. Patients were treated with pre-operative RT boost of 1332 cGy in 4 fractions, followed by lumpectomy and post-operative adjuvant whole breast RT to 3663 cGy in 11 fractions. The primary outcome was to demonstrate the incidence of grade 3 or more wound complications was not inferior to lumpectomy with standard postoperative whole breast RT and boost (6- 20%). We also compared the pre-op boost volume to a mock boost volume that would have been done post-operatively. RESULTS: Fifty-five women were enrolled between June 2021 and October 2022. Median age was 64 years-old, (range 40-77). Forty-three patients had invasive cancers and 5 had DCIS. Median clinical tumor size was 13 mm, (range 5-26). Grade 3 wound dehiscence requiring surgical revision occurred in one patient (2%). There were no other grade 3 adverse events. Three patients (6%) had grade 2 infections requiring antibiotics. The target boost volume was significantly lower that the mock post-operative volume (11cc vs. 56 cc; p <.001) Cosmetic outcome at 1st follow up was very good or excellent in 87% of patients and none had poor cosmetic outcome. CONCLUSION: The use of a pre-operative RT boost followed by whole breast RT as administered here resulted in an acceptable primary outcome with a similar rate of post-operative wound complications and smaller boost volume compared to standard postoperative RT. This approach is currently under consideration for cooperative group Phase III trial.

Molecular characterization, expression and in-silico analysis of fibrinogen-related protein 1 (frep1) in malaria vector Anopheles stephensi.

BACKGROUND: Fibrinogen-related protein 1 (frep1) is a member of the pattern-recognizing receptor family (PRR) which generates an innate immune response after recognizing the pattern associated molecular pattern (PAMP) that occurs on the surface of microorganisms. The main objective of this study is to characterize frep1 and its in-silico analysis in Anopheles stephensi. METHODS AND RESULT: The DNA was extracted from female Anopheles stephensi. PCR was performed for complete analysis of frep1 using specific primers. The gene sequence of frep1 was identified by Sanger sequencing. The bioinformatics structure analysis approach revealed the presence of 3 exons and 4 introns in the frep1. The sequence of frep1 was submitted to NCBI GeneBank with accession number ON817187.1. Quantitative real-time PCR was performed to analyze frep1 expression. At the developmental stage, frep1 is highly expressed in the L1 stage, egg, and adult female mosquito. In addition, frep1 is highly expressed in the tissue fat body, midgut, and salivary gland. After blood-fed, an upregulation of frep1 at 48 h in the midgut, and downregulation in fat body were observed at different time intervals. CONCLUSION: The genomic data of frep1 is encoded by 12,443 bp. The frep1 has a significant role in the early metamorphosis. Its expression in fat body and midgut suggests it could be important for fat metabolism and post-blood digestion. The conserved domain could be targeted for vector control. Further study is required to elucidate its function against malaria parasites to confirm its agonist role in malaria transmission.

A pan-cancer analysis of Wnt family member 7B in human cancers.

Background: Previous studies have highlighted the crucial role of Wnt7B in the development of various cancers, including breast, pancreatic, and gastric cancers. However, research into the involvement of Wnt7B is often confined to specific tumor types, with a noticeable lack of comprehensive studies spanning multiple cancer forms. The potential of Wnt7B as a diagnostic or prognostic cancer biomarker has not been fully explored. Methods: In this study, we combined bioinformatics and immunohistochemistry analyses to examine the expression patterns and functions of Wnt7B in cancerous and adjacent noncancerous tissues across a range of tumors. Results: Our data indicate that Wnt7B may serve as a novel prognostic biomarker and therapeutic target in certain cancers. Conclusion: We found significant upregulation of Wnt7B expression levels in the majority of cancer cases examined. Furthermore, Wnt7B can influence cancer prognosis by modulating the tumor microenvironment, immune cell infiltration, and tumor stemness, among other factors. Additionally, we examined the associations between anticancer drug sensitivity and Wnt7B expression, which could aid in the development of more precise clinical therapies.

Quadruplet therapy for newly diagnosed myeloma: comparative analysis of sequential cohorts with triplet therapy lenalidomide, bortezomib and dexamethasone (RVd) versus daratumamab with RVD (DRVd) in transplant-eligible patients.

Lenalidomide, bortezomib, and dexamethasone (RVd) have previously been established as standard-of-care induction therapy for newly diagnosed multiple myeloma (NDMM). More recently, randomized phase 3 data have demonstrated the benefit of the addition of daratumumab (Dara-RVd) to the RVd backbone in terms of improved both depth of response and long-term survival benefit as measured by progression-free survival (PFS). Our group has previously published on a historical cohort of 1000 NDMM patients uniformly treated with RVd induction with impressive both PFS and overall survival. Here, we present a comparative analysis of our RVd cohort with a recent cohort of 326 patients induced with Dara-RVd at our institution with intent to transplant. This analysis demonstrates the utility of this regimen in real-world clinical practice and provides additional insights into D-RVd performance in patient subsets often underrepresented in clinical trials, as well as the impact of daratumumab in maintenance for NDMM patients.

Abemaciclib Therapy Using the MonarchE Criteria Results in Large Numbers of Excess Axillary Node Clearances-Time to Pause and Reflect?

The monarchE study added the CDK4/6 inhibitor abemaciclib to the care of women with oestrogen-positive (ER+) breast cancers. Eligibility required meeting monarchE criteria-either >3 positive axillary nodes, or 1-3 positive sentinel nodes (SNB+) with tumour size >50 mm or grade 3 cancers. Women were advised to proceed to completion axillary node clearance (cANC) if size/grade criteria were not fulfilled for >3 positive nodes to be identified. However, cANC is associated with significant morbidity, conflicting with the potential benefits of abemaciclib. We analysed data of 229 consecutive women (2016-2022) with ER+ breast cancer and SNB+ who proceeded to cANC, keeping with contemporary treatment guidelines. We used this cohort to assess numbers that, under national guidance in place currently, would be advised to undergo cANC solely to check eligibility for abemaciclib treatment. Using monarchE criteria, 90 women (39%) would have accessed abemaciclib based on SNB+ and size/grade, without cANC. In total, 139 women would have been advised to proceed to cANC to check eligibility, with only 15/139 (11%) having >3 positive nodes after sentinel node biopsy and cANC. The remaining 124 (89%) would have undergone cANC but remained ineligible for abemaciclib. Size, age, grade, and Ki67 did not predict >3 nodes at cANC. Following cANC, a large majority of women with ER+, <50 mm, and grade 1-2 tumours remain ineligible for abemaciclib yet are subject to significant morbidity including lifelong lymphoedema risk. The monarchE authors state that 15 women need abemaciclib therapy for 1 to clinically benefit. Thus, in our cohort, 139 women undergoing cANC would lead to one woman benefitting.

How to rescue a DreaMM deferred .

The recently published DreaMM-7 and -8 trials1,2 demonstrate the benefit of triplet combination regimens including the anti-BCMA antibody drug conjugate belantamab mafodotin. Here, we describe the findings of these trials including efficacy and safety data and provide commentary on the implications for future use of belantamab in the relapsed myeloma space.

Intercellular nanotube-mediated mitochondrial transfer enhances T cell metabolic fitness and antitumor efficacy.

Mitochondrial loss and dysfunction drive T cell exhaustion, representing major barriers to successful T cell-based immunotherapies. Here, we describe an innovative platform to supply exogenous mitochondria to T cells, overcoming these limitations. We found that bone marrow stromal cells establish nanotubular connections with T cells and leverage these intercellular highways to transplant stromal cell mitochondria into CD8+ T cells. Optimal mitochondrial transfer required Talin 2 on both donor and recipient cells. CD8+ T cells with donated mitochondria displayed enhanced mitochondrial respiration and spare respiratory capacity. When transferred into tumor-bearing hosts, these supercharged T cells expanded more robustly, infiltrated the tumor more efficiently, and exhibited fewer signs of exhaustion compared with T cells that did not take up mitochondria. As a result, mitochondria-boosted CD8+ T cells mediated superior antitumor responses, prolonging animal survival. These findings establish intercellular mitochondrial transfer as a prototype of organelle medicine, opening avenues to next-generation cell therapies.

A Computational Approach in the Systematic Search of the Interaction Partners of Alternatively Spliced TREM2 Isoforms.

Alzheimer's disease is the most common form of dementia, characterized by the pathological accumulation of amyloid-beta (Aß) plaques and tau neurofibrillary tangles. Triggering receptor expressed on myeloid cells 2 (TREM2) is increasingly recognized as playing a central role in Aß clearance and microglia activation in AD. The TREM2 gene transcriptional product is alternatively spliced to produce three different protein isoforms. The canonical TREM2 isoform binds to DAP12 to activate downstream pathways. However, little is known about the function or interaction partners of the alternative TREM2 isoforms. The present study utilized a computational approach in a systematic search for new interaction partners of the TREM2 isoforms by integrating several state-of-the-art structural bioinformatics tools from initial large-scale screening to one-on-one corroborative modeling and eventual all-atom visualization. CD9, a cell surface glycoprotein involved in cell-cell adhesion and migration, was identified as a new interaction partner for two TREM2 isoforms, and CALM, a calcium-binding protein involved in calcium signaling, was identified as an interaction partner for a third TREM2 isoform, highlighting the potential role of cell adhesion and calcium regulation in AD.

Enhancing topical delivery of ISRIB: Optimizing cream formulations with chemical enhancers and pH adjustment.

Chemical warfare agents, particularly vesicants like lewisite, pose a threat due to their ability to cause skin damage through accidental exposure or deliberate attacks. Lewisite rapidly penetrates the skin, causing inflammation and blistering. This study focuses on developing a cream formulation of a therapeutic agent, called integrated stress response inhibitor (ISRIB), to treat lewisite-induced injuries. Moreover, animal studies demonstrate a molecular target engagement (ISR) and significant efficacy of ISRIB against lewisite-induced cutaneous injury. The goal of this formulation is to enhance the delivery of ISRIB directly to affected skin areas using an oil-in-water cream emulsion system. We investigated various excipients, including oils, surfactants, emollients, and permeation enhancers, to optimize ISRIB's solubility and penetration through the skin. The result of this study indicated that the optimal formulation includes 30 % w/w of N-Methyl-2-pyrrolidone, dimethyl sulfoxide and Azone® at a pH of 5. 5. It delivered the highest amount of ISRIB into the skin, demonstrating highest skin absorption with no detectable systemic exposure. Additionally, characterization of the cream, including texture analysis, emulsion type, and content uniformity, confirmed its' suitability for topical application. These findings suggest that ISRIB cream formulation is a promising approach for the localized treatment of skin injuries caused by lewisite.

A prospective longitudinal investigation of the trajectory of obsessive-compulsive symptoms during adolescence.

Obsessive-compulsive symptoms (OCS) increase with age during childhood and adolescence, and subthreshold OCS in childhood associate with a higher probability of obsessive-compulsive disorder (OCD) diagnosis in adulthood. Additionally, average age of onset for OCD is in adolescence, with the majority of OCD cases emerging by early adulthood. Despite these trends, the specific course of OCS development in adolescence is relatively unknown. To this end, the present prospective longitudinal study used latent growth mixture modeling and a diverse community sample of 3,335 high schoolers to identify and characterize growth trajectories of OCS across middle to late adolescence. Results identified three trajectories: High-but-Remitting, Moderate-but-Escalating, and Low-and-Stable. Results also indicated age, gender, anxiety sensitivity, and distress tolerance as significant predictors of trajectory group membership, such that younger age and being female predicted classification in the High-but Remitting group, greater anxiety sensitivity predicted classification in both the High-but-Remitting and Moderate-but Escalating groups, and greater distress tolerance predicted a lower likelihood of classification in the High-but-Remitting and Moderate-but-Escalating groups. Taken together, these trajectories have illustrated the temporal course and development of OCS across key developmental years. Moreover, the trajectories and their corresponding predictors may help identify adolescents who are particularly vulnerable to developing OCD.

From Cirrhosis to the Dysbiosis (A Loop of Cure or Complications?).

Gut dysbiosis and liver cirrhosis are two corelated complications that highly disturbs the metabolism of a normal human body. Liver cirrhosis is scarring of the hepatic tissue and gut dysbiosis is the imbalance in the microbiome of the gut. Gut dysbiosis in cirrhosis occurs due to increased permeability of the intestinal membrane which might induce immune responses and damage the normal functioning of the body. Dysbiosis can cause liver damage from cirrhosis and can further lead to liver failure by hepatocellular carcinoma. In this review we discuss if eubiosis can revert the poorly functioning cirrhotic liver to normal functioning state? A normal microbiome converts various liver products into usable forms that regulates the overgrowth of microbiome in the gut. The imbalance caused by dysbiosis retards the normal functioning of liver and increases the complications. To correct this dysbiosis, measures like use of antibiotics with probiotics and prebiotics are used. This correction of the gut microbiome serves as a ray of hope to recover from this chronic illness. In case of alcohol induced liver cirrhosis, intervention of microbes can possibly be helpful in modulating the addiction as well as associated complications like depression as microbes are known to produce and consume neurotransmitters that are involved in alcohol addiction. Hence a correction of gut liver brain axis using microbiome can be a milestone achieved not only for treatment of liver cirrhosis but also for helping alcohol addicts quit and live a healthy or at least a near healthy life.

Nourishing the Infant Gut Microbiome to Support Immune Health: Protocol of SUN (Seeding Through Feeding) Randomized Controlled Trial.

BACKGROUND: The introduction of complementary foods during the first year of life influences the diversity of the gut microbiome. How this diversity affects immune development and health is unclear. OBJECTIVE: This study evaluates the effect of consuming kumara or kumara with added banana powder (resistant starch) compared to a reference control at 4 months post randomization on the prevalence of respiratory tract infections and the development of the gut microbiome. METHODS: This study is a double-blind, randomized controlled trial of mothers and their 6-month-old infants (up to n=300) who have not yet started solids. Infants are randomized into one of 3 groups: control arm (C), standard kumara intervention (K), and a kumara intervention with added banana powder product (K+) to be consumed daily for 4 months until the infant is approximately 10 months old. Infants are matched for sex using stratified randomization. Data are collected at baseline (prior to commencing solid food) and at 2 and 4 months after commencing solid food (at around 8 and 10 months of age). Data and samples collected at each timepoint include weight and length, intervention adherence (months 2 and 4), illness and medication history, dietary intake (months 2 and 4), sleep (diary and actigraphy), maternal dietary intake, breast milk, feces (baseline and 4 months), and blood samples (baseline and 4 months). RESULTS: The trial was approved by the Health and Disability Ethics Committee of the Ministry of Health, New Zealand (reference 20/NTA/9). Recruitment and data collection did not commence until January 2022 due to the COVID-19 pandemic. Data collection and analyses are expected to conclude in January 2024 and early 2025, respectively. Results are to be published in 2024 and 2025. CONCLUSIONS: The results of this study will help us understand how the introduction of a specific prebiotic complementary food affects the microbiota and relative abundances of the microbial species, the modulation of immune development, and infant health. It will contribute to the expanding body of research that aims to deepen our understanding of the connections between nutrition, gut microbiota, and early-life postnatal health. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12620000026921; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378654. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/56772.