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Poplar plantations cover 31.4 million ha around the world and supply timber for paper, sawn wood and other wood-based products. In each region where poplars are planted, it is possible to identify “model clones” which are massively adopted by foresters. Improving the rationale of clone selection in breeding programs requires a comprehensive understanding of the physiological traits that explain the differences in genotypes growth. Moreover, given that growth is related to the use of resources (water, light and nutrients) we also need to determine which morphological and physiological traits explain the model condition of most widespread clones. A controlled-condition study was carried out to evaluate eight Populus deltoides and two Populus × canadensis clones, including the model Populus deltoides €˜Australiano 129/60’. For each clone, physiological and morphological traits related to biomass partitioning (roots, stem and leaf dry mass), growth (height, diameter), light use (leaf area duration, leaf size, net photosynthetic rate), water use (stem hydraulic conductivity, water consumption) and nutrient use (nitrogen and phosphorus concentrations) were measured. High variability in the physiology and morphology was observed among clones, and similar and contrasting clones in relation to the model clone were identified. Similarities among clones varied depending on the characteristic being evaluated at the time-water use, light use or nutrient use. The results showed that variability not only relates to visible phenotype, but also to functionality. This information is significant since the breeding programs can evaluate non-traditional traits and select genotypes which are similar or complementary to the model clone. The characterization of model clones is key for breeding programs which seek new candidates taking into account the use of water, nutrients and light. It is also important because it helps explain why foresters prefer one clone over others. Knowledge about functional variability within clones of the same species enables foresters to conduct more intelligent and site-specific silviculture and to optimize the genotype selection in breeding programs.

This research explores the Impact of the TikTok Application on Second Language Acquisition among Grade 10 students at the Central Bicol State University of Agriculture – Sipocot Laboratory High School. Employing a descriptive correlation method, the study aimed to discern the perceived impact of TikTok on second language acquisition, assess its utilization concerning grammar, vocabulary, and pronunciation, and establish a significant relationship between TikTok use and language acquisition. Various statistical treatments were used, i.e., weighted mean and ranking technique and Pearson’s R. The data were collected from 40 Grade 10 students using a researcher-made survey questionnaire and Google Form. The results indicated a consistently high utilization of TikTok across grammar, vocabulary, and pronunciation domains, with an overall weighted mean of 3.29, interpreted as ‘always.’ Significantly, the relationship between TikTok usage and its perceived impact on second language acquisition was affirmed (grammar p-value = 0.000

Francisca Campos,1 Javiera A Álvarez,1 Javiera Ortiz-Severín,1 Macarena A Varas,1 Carlos F Lagos,2 Ricardo Cabrera,3 Sergio A Álvarez,4 Francisco P Chávez11Laboratorio de Microbiología de Sistemas, Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Santiago de Chile, Chile; 2Chemical Biology & Drug Discovery Laboratory, Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago de Chile, Chile; 3Laboratorio de Bioquímica y Biología Molecular, Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Santiago de Chile, Chile; 4Laboratorio de Microbiología, Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas Y Farmacéuticas, Universidad de Chile, Santiago de Chile, ChileAbstract: Inorganic polyphosphate (polyP) and its metabolic enzymes are important in several cellular processes related with virulence and antibiotic susceptibility. Accordingly, bacterial polyP synthesis has been proposed as a good target for designing novel antivirulence molecules as alternative to conventional antibiotics. In most pathogenic bacteria, polyphosphate kinase 1 (PPK1), in charge of polyP synthesis from ATP, is widely conserved. Current colorimetric and radioactive polyP synthesis enzymatic assays are not suitable for high-throughput screening of PPK1 inhibitors. Given the ability of polyP to modify the excitation-emission spectra of DAPI (4ʹ-6-diamidino-2-phenylindole), a fluorescence assay was previously developed by using a purified recombinant PPK1 enzyme from Escherichia coli. In this work we have developed a suitable methodology for high-throughput measurement of E. coli PPK1 activity. This platform can be used for the screening putative antimicrobial molecules for related enteropathogenic bacteria.Keywords: antivirulence, antimicrobial, affinity purification, polyphosphate kinase, DAPI, fluorescence enzymatic activity

Background: This study was conducted to compare the antiseptic efficacy of sodium hypochlorite of electrochemical production with that of povidone-iodine in human voluntaries. Methods: Three areas of 25 cm2 each were selected from the forearms; 1 was designated as control to determine the baseline bacterial count; and 2 more were selected to swab 10% povidone-iodine or 10% sodium hypochlorite. Every volunteer was studied on 3 separated occasions. Quantitative skin cultures were performed on agar plates containing a neutralizer. Results: Forty-eight healthy subjects were enrolled for a total of 144 determinations for every antiseptic and control. The bacterial counts from the control areas showed a median of 1500 colony-forming units (CFU)/cm2. For the areas treated with sodium hypochlorite, the median was 192 CFU/cm2. For the areas treated with povidone-iodine, the median was 231 CFU/cm2. When the colony counts for the areas treated with antiseptics were compared with those of the controls, the difference was significant (Kruskal-Wallis test (H) = 55.7, P < .001). The difference in counts between the areas treated with antiseptics was not significant (difference in z values <1960). Conclusion: The present study did not find differences in antiseptic action between 10% povidone iodine and 10% sodium hypochlorite. [ABSTRACT FROM AUTHOR]

Background Pyogenic liver abscess is a life-threatening disease. Few studies have specifically explored the way in which the clinical features and management of elderly patients with pyogenic liver abscess differ from those of younger individuals. Methods A retrospective study was undertaken to evaluate whether older patients with pyogenic liver abscess have distinctive presenting features or whether their management and outcome differ from that of younger patients. A total of 133 patients with liver abscess treated in five hospitals during 13 years comprised two groups: 78 patients aged 60 years or above (older group) and 55 patients below age 60 years (younger group). Clinical features, laboratory data, imaging and microbiological findings, management and outcome were determined in each group. Results The older group contained more patients with associated diseases (p = 0.03), nausea and vomiting at presentation (p = 0.02), higher APACHE II (Acute Physiological and Chronic Health Evaluation II scale) score (p < 0.001) and blood urea nitrogen (p < 0.001) and serum creatinine levels (p = 0.002). Multiple abscess (p = 0.05) and bilobar (p = 0.03) abscess were also commoner in this group. By contrast, in the younger group men predominated (p = 0.01), and there was a higher overall complication rate (p = 0.05). Time to diagnosis, hospital mortality rate and other variables analysed were similar in both groups. Discussion Elderly patients with pyogenic liver abscess have some subtle differences in clinical and laboratory presentation, but these do not appear to delay diagnosis. Active management is tolerated well, with a lower morbidity rate than in younger patients and no difference in the mortality rate. [ABSTRACT FROM AUTHOR]

Lumbar spine stenosis most commonly affects the middle-aged and elderly population. Entrapment of the cauda equina roots by hypertrophy of the osseous and soft tissue structures surrounding the lumbar spinal canal is often associated with incapacitating pain in the back and lower extremities, difficulty ambulating, leg paresthesias and weakness and, in severe cases, bowel or bladder disturbances. The characteristic syndrome associated with lumbar stenosis is termed neurogenic intermittent claudication. This condition must be differentiated from true claudication, which is caused by atherosclerosis of the pelvofemoral vessels. Although many conditions may be associated with lumbar canal stenosis, most cases are idiopathic. Imaging of the lumbar spine performed with computed tomography or magnetic resonance imaging often demonstrates narrowing of the lumbar canal with compression of the cauda equina nerve roots by thickened posterior vertebral elements, facet joints, marginal osteophytes or soft tissue structures such as the ligamentum flavum or herniated discs. Treatment for symptomatic lumbar stenosis is usually surgical decompression. Medical treatment alternatives, such as bed rest, pain management and physical therapy, should be reserved for use in debilitated patients or patients whose surgical risk is prohibitive as a result of concomitant medical conditions. [ABSTRACT FROM AUTHOR]

This research was conducted in prebeneficiadora coffee plant of UAC-CP, located in the community of Carmen Pampa, Coroico Municipality, Nor Yungas of La Paz department. The objective was to determine the efficiency of wastewater treatment prebeneficiado coffee because it is not known to be effective in reducing the level of contamination of treated wastewater, and according to the results to correct and / or validate directly model system in place. For their study was established seven sampling points within the system of treatment and four replications were made at different times and with different amounts of coffee cherry. We evaluated the parameters of temperature, pH, settleable solids, total suspended solids, fixed and volatile, biochemical oxygen demand, chemical oxygen demand and dissolved oxygen. The temperature of wastewater entering the system has recorded 16.5 o C, increasing during the treatment process at 17.5 °C and record the output is 16.5 ºC. The pH increased from 4.51 to 6.04 which occurred at the last two gaps oxygenation and not in the neutralization tank. Settleable solids (SS) increased from 0.1 mg / L to 0.15 mg / L, which was recorded at the lakes of oxygen, is attributed to the drag of fine gravel. Total suspended solids (TSS) have been reduced from 1927.5 mg / L to 299 mg / L gradually throughout the treatment process. Fixed suspended solids (SSF) were reduced from 137.5 mg / L to 58.5 mg / L. Volatile suspended solids (VSS) were reduced from 1790 mg / L to 240.5 mg / L. Biochemical oxygen demand (BOD) was reduced from 6102.5 mg O2 / L to 1245 mg O2 / L. The chemical oxygen demand (COD) was reduced from 9800 mg O2 / L to 1658.75 mg O2 / L. Dissolved oxygen (DO) increased from 0 to 2.4 mg O2 / L, in the last two gaps in oxygenation, due to the reduction of solids and chemical oxygen demand and biochemical oxygen. Of the nine parameters measured, six meet the maximum permissible values for download in source receptor (stream) and three of them are outside the parameter according to the regulation of Law 1333.

Uno de los mayores problemas de la fertilidad de los suelos de los Llanos Orientales, en la Orinoquia colombiana, es la alta fijación del fósforo ocasionada principalmente por los compuestos presentes en su fracción arcilla. El uso de mezclas de materiales orgánicos y minerales puede ayudar a disminuir esta fijación, para lo que se utilizaron dos materiales orgánicos –gallinaza y compost– y dos materiales inorgánicos –cal y superfosfato triple (SPT)– y se estableció un total de 13 tratamientos dispuestos en bloques al azar y compuestos por las diferentes combinaciones entre fertilizantes minerales y orgánicos. La medición del fraccionamiento de P se hizo al momento de la siembra y a las 10 semanas de ésta, utilizando la secuencia propuesta por Hedley. Las variables de respuesta del experimento fueron el P disponible, biológicamente disponible, orgánico fácilmente mineralizable, inorgánico ligado a óxidos de Fe y Al, orgánico ligado a sustancias húmicas, inorgánico ligado al calcio y no disponible. Los valores más altos en todas las fracciones de P correspondieron a los tratamientos que combinan un material orgánico y un fertilizante mineral, mejorando la disponibilidad de P para las plantas. El uso de materiales orgánicos con fuentes minerales hizo disminuir la retención de P por parte de óxidos de Fe y Al, aumentando el P disponible en el suelo yel P total. No se logró modificar la cantidad inicial y la cantidad final de P no disponible, así como tampoco se encontraron diferencias significativas entre tratamientos en esta fracción.

El presente trabajo se desarrolló en los laboratorios de Suelos de la Facultad de Agronomía de la Universidad Nacional de Colombia, sede Bogotá, con el propósito de estudiar la respuesta de un suelo salino a la aplicación de agua de riego con diferentes tratamientos de temperatura y frecuencia. El suelo utilizado es un Humic Haplustands tomado del lote 4 del Centro Agropecuario Marengo. El diseño experimental utilizado fue completamente al azar, con arreglo factorial 3 x 2, en el que el primer factor fue la temperatura del agua de riego (18, 23 y 30 ºC) y el segundo factor, el fraccionamiento de la lámina de riego (lámina fraccionada y lámina total aplicada). Todos los tratamientos fueron sometidos a una corriente directa de 2 V. Las variables analizadas para cada tratamiento fueron: pH, conductividad eléctrica, sulfatos, cloruros, carbonatos, bicarbonatos y bases totales (Ca, Mg, Na, K), medidas en el extracto de saturación, antes y después de aplicar los tratamientos. El análisis de resultados permitió concluir que la mayor reducción en los contenidos de Ca y Mg se presentó cuando el agua de riego se encontraba a 30 ºC; en las demás variables medidas no se presentó respuesta a los cambios de temperatura. La aplicación de 2 V de corriente directa disminuyó significativamente los contenidos de Ca, Mg, Na, K y Cl, así como los valores de la conductividad eléctrica. En cuanto a las frecuencias de aplicación de las láminas de riego, ninguna de las variables mostró respuesta.

Glycosylphosphatidylinositols (GPIs) are highly conserved anchors for eukaryotic cell surface proteins. The apicomplexan parasite, Toxoplasma gondii , is a widespread intracellular parasite of warm-blooded animals whose plasma membrane is covered with GPI-anchored proteins, and free GPIs called GIPLs. While the glycan portion is conserved, species differ in sidechains added to the triple mannose core. The functional significance of the Glcα1,4GalNAcβ1- sidechain reported in Toxoplasma gondii has remained largely unknown without understanding its biosynthesis. Here we identify and disrupt two glycosyltransferase genes and confirm their respective roles by serology and mass spectrometry. Parasites lacking the sidechain on account of deletion of the first glycosyltransferase, PIGJ, exhibit increased virulence during primary and secondary infections, suggesting it is an important pathogenesis factor. Cytokine responses, antibody recognition of GPI-anchored SAGs, and complement binding to PIGJ mutants are intact. By contrast, the scavenger receptor CD36 shows enhanced binding to PIGJ mutants, potentially explaining a subtle tropism for macrophages detected early in infection. Galectin-3, which binds GIPLs, exhibits an enhancement of binding to PIGJ mutants, and the protection of galectin-3 knockout mice from lethality suggests that Δ pigj parasite virulence in this context is sidechain dependent. Parasite numbers are not affected by Δ pigj early in the infection in wild-type mice, suggesting a breakdown of tolerance. However, increased tissue cysts in the brains of mice infected with Δ pigj parasites indicate an advantage over wild-type strains. Thus, the GPI sidechain of T. gondii plays a crucial and diverse role in regulating disease outcomes in the infected host.IMPORTANCEThe functional significance of sidechain modifications to the glycosylphosphatidylinositol (GPI) anchor in parasites has yet to be determined because the glycosyltransferases responsible for these modifications have not been identified. Here we present identification and characterization of both Toxoplasmsa gondii GPI sidechain-modifying glycosyltransferases. Removal of the glycosyltransferase that adds the first GalNAc to the sidechain results in parasites without a sidechain on the GPI, and increased host susceptibility to infection. Loss of the second glycosyltransferase results in a sidechain with GalNAc alone, and no glucose added, and has negligible effect on disease outcomes. This indicates GPI sidechains are fundamental to host-parasite interactions., Competing Interests: The authors declare no conflict of interest.

The aim of this study was to investigate the impact of different concentrations (3% and 6%) of two ingredients (paste and flour) obtained from the valorization of date fruit coproducts on the nutritional (proximate composition and mineral profile), technological (coagulation curve, pH, acidity, sugar and organic acid content and syneresis), physicochemical (color, water activity and texture), microbiological and sensory properties of goat's yogurt during 21 days of refrigerated storage. Both ingredients enhanced the growth and stability of the yogurt starter culture, thereby improving the probiotic potential of date-added yogurts. Physicochemically, the addition of date flour (at both concentrations) induces stronger modifications (texture, color and syneresis) in yogurts than the date paste. During storage, date paste reduced the syneresis and hence maintained yogurts' physical quality. Consumers preferred the yogurts with date paste (3% and 6%) rather than with date flour, because its addition led to a more brownish color and granular texture., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Sex-specific, long-term, body weight change in persons with HIV (PWH) following switch to regimens containing integrase strand-transfer inhibitors (INSTIs) is unknown., Methods: We compared PWH enrolled in the MACS/WIHS Combined Cohort Study (2007-2020) who switched/added an INSTI to their antiretroviral therapy (ART) to those remaining on non-INSTI ART and to people without HIV (PWOH), by sex. Follow-up time was time since switch visit (or comparable visit in controls). Linear regression mixed effect models assessed the effects of sex, group (INSTI, non-INSTI, PWOH), and time upon weight and anthropometric measurements (waist, hip, thigh)., Results: Of 3464 participants included, women (411 INSTI, 709 Non-INSTI, 818 PWOH) compared to men (223 INSTI, 412 Non-INSTI, 891 PWOH) were younger (47.2 years vs 54.5), majority non-Hispanic Black (65 vs 23%), and had higher mean BMI (31.5 kg/m2 vs 26.9), respectively. Women switching to INSTIs experienced greater absolute and % weight gain compared to men at 5 years: +3.0 kg (95% CI 2.1-3.9) vs +1.8 kg (0.7-2.9) and +4.6% (3.5-5.7) vs +2.3% (1.0-3.6), respectively, [sex*time*study group interaction, p<0.01]. Compared to men, women switching to INSTIs experienced greater hip and thigh circumference gain at 5 years: +2.6 cm (95% CI 1.6-3.6) vs +1.2 cm (0.3-2.1) and +1.5 cm (0.7-2.2) vs -0.2 cm (-0.9, 0.5), respectively, but there were no significant sex differences in waist circumference or waist-hip ratio., Conclusions: Weight change among PWH over 5 years after switch to INSTI was 2-fold higher in women than men. The cardio-metabolic implications of this difference in weight gain remain unknown., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

XK disease is a very rare, multi-system disease, which can present with a wide spectrum of symptoms. This disorder can also be identified pre-symptomatically with the incidental detection of serological abnormalities when typing erythrocytes in peripheral blood, or on other routine laboratory testing. Increasing awareness of this disorder and improved access to genetic testing are resulting in increasing identification of affected patients and families. Here we provide updates to some previously-reported families and patients and provide additional clinical details. We also report four new cases with a variety of presentations, one of whom had a novel mutation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Walker, Barreto, Bateman, Bustamante, Chiu, Feitell, Frey, Guerra, Guerrero, Jung, Maldonado, Meyer, Miranda, McFarland, Oates, Ochoa, Olsson, Paucar, Proschle, Sammler, Troncoso, Wu-Wallace, Young, Vege, Westhoff and Danek.)

Background: Respiratory syncytial virus (RSV) is associated with substantial morbidity among infants. This study modelled the potential public health and economic impact of nirsevimab, a long-acting monoclonal antibody, as an immunoprophylactic strategy for all infants in Spain in their first RSV season., Methods: A static decision-analytic model of the Spanish birth cohort during its first RSV season was developed to estimate the impact of nirsevimab on RSV-related health events and costs versus the standard of practice (SoP). Spain-specific costs and epidemiological data were used as model inputs. Modelled outcomes included RSV-related outpatient visits, emerging room (ER) visits, hospitalisations - including pediatric intensive care unit (PICU) admission, mechanical ventilation, and inpatient mortality., Results: Under the current SoP, RSV caused 151,741 primary care visits, 38,798 ER visits, 12,889 hospitalisations, 1,412 PICU admissions, and 16 deaths over a single season, representing a cost of €71.8 million from a healthcare payer perspective. Universal immunisation of all infants with nirsevimab was expected to prevent 97,157 primary care visits (64.0% reduction), 24,789 ER visits (63.9%), 8,185 hospitalisations (63.5%), 869 PICU admissions (61.5%), and 9 inpatient deaths (52.6%), saving €47.8 million (62.4%) in healthcare costs., Conclusions: These results suggest that immunisation with nirsevimab of all infants experiencing their first RSV season in Spain is likely to prevent thousands of RSV-related health events and save considerable costs versus the current SoP., (© 2024. The Author(s).)

Advances in cystic fibrosis (CF) diagnostics and therapeutics have led to improved health and longevity, including increased body weight and decreased malnutrition in people with CF. Highly effective CFTR modulator therapies (HEMT) are associated with increased weight through a variety of mechanisms, accelerating trends of overweight and obesity in the CF population. Higher body mass index (BMI) is associated with improved pulmonary function in CF, yet the incremental improvement at overweight and obese BMIs is not clear. Improvements in pulmonary health with increasing BMI are largely driven by increases in fat-free mass (FFM), and impact of HEMT on FFM is uncertain. While trends toward higher weight and BMI are generally seen as favorable in CF, the increased prevalence of overweight and obesity has raised concern for potential risk of traditional age- and obesity-related comorbidities. Such comorbidities, including impaired glucose tolerance, hypertension, cardiac disease, hyperlipidemia, fatty liver, colon cancer, and obstructive sleep apnea, may occur on top of pre-existing CF-related comorbidities. CF nutrition recommendations are evolving in the post-modulator era to more individualized approaches, in contrast to prior blanket high-fat, high-calorie prescriptions for all. Ultimately, it will be essential to redefine goals for optimal weight and nutritional status to allow for holistic health and aging in people with CF., (© 2023 Wiley Periodicals LLC.)

Introduction: Thiamine (Vitamin B1) is an essential micronutrient and is classically considered a co-factor in energy metabolism. The association between thiamine status and whole-body metabolism in critical illness has not been studied., Objectives: To determine association between whole blood thiamine pyrophosphate (TPP) concentrations and plasma metabolites and connected metabolic pathways using high resolution metabolomics (HRM) in critically ill patients., Methods: Cross-sectional study performed at Erciyes University Hospital, Kayseri, Turkey and Emory University, Atlanta, GA, USA. Participants were critically ill adults with an expected length of intensive care unit stay longer than 48 h and receiving chronic furosemide therapy. A total of 76 participants were included. Mean age was 69 years (range 33-92 years); 65% were female. Blood for TPP and metabolomics was obtained on the day of ICU admission. Whole blood TPP was measured by HPLC and plasma HRM was performed using liquid chromatography/mass spectrometry. Data was analyzed using regression analysis of TPP levels against all plasma metabolomic features in metabolome-wide association studies (MWAS). MWAS using the highest and lowest TPP concentration tertiles was performed as a secondary analysis., Results: Specific metabolic pathways associated with whole blood TPP levels in regression and tertile analysis included pentose phosphate, fructose and mannose, branched chain amino acid, arginine and proline, linoleate, and butanoate pathways., Conclusions: Plasma HRM revealed that thiamine status, determined by whole blood TPP concentrations, was significantly associated with metabolites and metabolic pathways related to metabolism of energy, carbohydrates, amino acids, lipids, and the gut microbiome in adult critically ill patients., (© 2024. The Author(s).)

Background: Recent data have demonstrated that in locally advanced rectal cancer (LARC), a total neoadjuvant therapy (TNT) approach improves compliance with chemotherapy and increases rates of tumor response compared to neoadjuvant chemoradiation (CRT) alone. They further indicate that the optimal sequencing of TNT involves consolidation (rather than induction) chemotherapy to optimize complete response rates. Data, largely from retrospective studies, have also shown that patients with clinical complete response (cCR) after TNT may be managed safely with the watch and wait approach (WW) instead of preemptive total mesorectal resection (TME). However, the optimal consolidation chemotherapy regimen to achieve cCR has not been established, and a randomized clinical trial has not robustly evaluated cCR as a primary endpoint. Collaborating with a multidisciplinary oncology team and patient groups, we designed this NCI-sponsored study of chemotherapy intensification to address these issues and to drive up cCR rates, to provide opportunity for organ preservation, improve quality of life for patients and improve survival outcomes., Methods: In this NCI-sponsored multi-group randomized, seamless phase II/III trial (1:1), up to 760 patients with LARC, T4N0, any T with node positive disease (any T, N +) or T3N0 requiring abdominoperineal resection or coloanal anastomosis and distal margin within 12 cm of anal verge will be enrolled. Stratification factors include tumor stage (T4 vs T1-3), nodal stage (N + vs N0) and distance from anal verge (0-4; 4-8; 8-12 cm). Patients will be randomized to receive neoadjuvant long-course chemoradiation (LCRT) followed by consolidation doublet (mFOLFOX6 or CAPOX) or triplet chemotherapy (mFOLFIRINOX) for 3-4 months. LCRT in both arms involves 4500 cGy in 25 fractions over 5 weeks + 900 cGy boost in 5 fractions with a fluoropyrimidine (capecitabine preferred). Patients will undergo assessment 8-12 (± 4) weeks post-TNT completion. The primary endpoint for the phase II portion will compare cCR between treatment arms. A total number of 312 evaluable patients (156 per arm) will provide statistical power of 90.5% to detect a 17% increase in cCR rate, at a one-sided alpha = 0.048. The primary endpoint for the phase III portion will compare disease-free survival (DFS) between treatment arms. A total of 285 DFS events will provide 85% power to detect an effect size of hazard ratio 0.70 at a one-sided alpha of 0.025, requiring enrollment of 760 patients (380 per arm). Secondary objectives include time-to event outcomes (overall survival, organ preservation time and time to distant metastasis) and adverse event rates. Biospecimens including archival tumor tissue, plasma and buffy coat, and serial rectal MRIs will be collected for exploratory correlative research. This study, activated in late 2022, is open across the NCTN and had accrued 330 patients as of May 2024. Study support: U10CA180821, U10CA180882, U24 CA196171; https://acknowledgments.alliancefound.org ., Discussion: Building on data from modern day rectal cancer trials and patient input from national advocacy groups, we have designed The Janus Rectal Cancer Trial studying chemotherapy intensification via a consolidation chemotherapy approach with the intent to enhance cCR and DFS rates, increase organ preservation rates, and improve quality of life for patients with rectal cancer., Trial Registration: Clinicaltrials.gov ID: NCT05610163; Support includes U10CA180868 (NRG) and U10CA180888 (SWOG)., (© 2024. The Author(s).)

Background: People with cystic fibrosis (PwCF) have experienced substantial improvements in health following use of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies. However, less is known about how modulator therapies impact well-being., Methods: We used a cross-sectional observational study to identify relationships between CFTR modulator therapies, health-related quality of life (HRQoL), and well-being. Adult PwCF and caregivers of children with CF completed the Wellness in the Modulator Era (Well-ME) survey between June 22 and July 31, 2022. HRQoL was measured with PROMIS Global 10/Global 7 + 2 Parent Proxy. We used a mixed methods analysis to compare experiences and concerns of PwCF who currently (n = 665), no longer (n = 51), or never (n = 184) took modulator therapy., Results: Adult PwCF taking a modulator (n = 416) reported better PROMIS global physical health than those who no longer (n = 37) or never took a modulator (n = 94) and better PROMIS global mental health than those who never took a modulator. Caregiver-reported HRQoL was similar across children with CF who currently, no longer, or never took a modulator. PwCF taking a modulator reported larger improvements in physical health, quality of life, social well-being, and treatment burden than those who no longer or never took a modulator. Nearly one-quarter (23 %) of PwCF taking modulator therapy reported worsening of mental well-being., Conclusions: This study expands our knowledge of well-being among PwCF in the CFTR modulator era as reported by patients and parents. Findings lay the groundwork for establishing future research priorities, policy efforts, and communications in areas that improve well-being for PwCF., Competing Interests: Declaration of competing interest The authors of this manuscript would like to disclose the following conflict of interest: E.A. reports a salary from the Cystic Fibrosis Foundation. T.K. reports grants from the Cystic Fibrosis Foundation and the National Institutes of Health and consulting fees from the Cystic Fibrosis Foundation. J.K. reports grants from the Cystic Fibrosis Foundation (VANCIT23AO-LAD and NELSON20QI0). C.L. receives an honorarium from the Cystic Fibrosis Foundation for time spent developing a survey. C.R. reports a salary from the Cystic Fibrosis Foundation. E.Y. reports a salary from the Cystic Fibrosis Foundation. A.V.C. reports grants from the Cystic Fibrosis Foundation (VANCIT23AO-LAD and NELSON20QI0), along with an honorarium and reimbursement for personal travel expenses to attend the 2023 CF Foundation Therapeutics Development Network meeting. J.A. reports funding support from the Cystic Fibrosis Foundation and the National Institute of Health, grants from the Cystic Fibrosis Foundation and the National Institute of Health, consulting fees from Anagram Therapeutics, and holds a leadership role in The Obesity Society. C.B. reports grants to her institution from the Cystic Fibrosis Foundation, Vertex Pharmaceuticals, and AstraZeneca, and serves as a board member of the Cystic Fibrosis Foundation's Indiana Chapter. J.C. receives a salary from the Cystic Fibrosis Foundation. R.C. reports an honorarium from the Cystic Fibrosis Foundation for time spent developing a survey. C.F. reports a Cystic Fibrosis Foundation Center Grant for salary support as a CF center director and for the Cystic Fibrosis Foundation STRC. A.G. reports grants from the Cystic Fibrosis Foundation, Dutch Cystic Fibrosis Foundation, National Heart, Lung, and Blood Institute, and Vertex Pharmaceuticals, along with consulting fees and honoraria paid directly from Vertex Pharmaceuticals, Saudi Pediatric Pulmonology Association, and Virginia Commonwealth Universit, along with support to attend meetings from Cystic Fibrosis Foundation, European Cystic Fibrosis Society, French Cystic Fibrosis Society, as well as a Leadership position at European Cystic Fibrosis Society committee and Cystic Fibrosis Foundation committee chair, both providing institutional funding. C.G. reports funding and grants from the National Institutes of Health, FDA, and the Cystic Fibrosis Foundation, along with Consulting fees paid directly from Enterprise Therapeutics Honoraria from Gilead Sciences and Vertex Pharmaceutical, and support to attend meetings from Vertex Pharmaceuticals and Enterprise Therapeutics, as well as Serving as a DSMB Chair for a trial supported by Novartis and the European Commission. Deputy Editor, Annals of the ATS, and Stock in Air Therapeutics. All other authors have nothing to disclose, (Copyright © 2024. Published by Elsevier B.V.)

Background: Cystic fibrosis (CF) is a multi-organ disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). Individuals with CF often have gastrointestinal (GI) dysbiosis due to chronic inflammation and antibiotic use. Previous studies suggested a role for vitamin D in reversing the GI dysbiosis found in CF., Objective: To explore the potential role of a combination of high-dose oral cholecalciferol (vitamin D 3 ) and fermentable dietary fiber, inulin, to impact bacterial composition, richness, and diversity of intestinal and airway microbiota in adults with CF., Methods: This was a 2 × 2 factorial, double-blinded, placebo-controlled, randomized, pilot clinical trial in which adults with CF received oral cholecalciferol (vitamin D 3 ) (50,000 IU/week) and/or inulin (12 g/day) for 12 weeks. Thus, there were 4 study groups (n = 10 subjects per group); 1) placebo 2) vitamin D 3 3) inulin 4) vitamin D 3 plus inulin. Stool and sputum samples were collected at baseline (just before) and after the intervention and were analysed using 16S ribosomal RNA gene sequencing for gut and airway microbiota composition. Statistical analyses assessed alpha and beta diversity to evaluate microbial community changes., Results: Of a total of 254 screened participants, 40 eligible participants were randomized to one of the 4 treatment arms. Participants receiving vitamin D 3 plus inulin exhibited greater changes in microbiome indexes in both intestinal and airway relative to those in the other study groups. Specific taxonomic changes supported the potential beneficial influence of this combination to mitigate both intestinal and airway dysbiosis in adults with CF., Conclusion: This pilot study established that the combination of oral vitamin D 3 and the prebiotic inulin was well tolerated over 12 weeks in adults with CF and altered gut and airway bacterial communities. Future research appear warranted to define clinical outcomes and the role of microbiota changes therein with this approach., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Vin Tangpricha reports financial support was provided by Cystic Fibrosis Foundation. Vin Tangpricha reports financial support was provided by National Institutes of Health. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Background and Objectives: Medical and public recognition of "long-COVID or post-COVID syndrome", as well as its impact on the quality of life (QoL), is required to better address the disease burden. Objectives: We aimed to describe the persistence of COVID-19 symptoms and QoL among patients at three and twelve months after their discharge from the hospital. Materials and Methods: We conducted an observational, prospective, and longitudinal analytic study from September 2021 to April 2022. To measure QoL, we used a validated version of the 36-item Short-Form Health Survey (SF-36). Results: We included 68 patients in the study. A total of 54 (79.4%) patients reported at least one persistent symptom at three months vs. 52 (76.4%) at twelve months ( p = 0.804). Some persistent symptoms (myalgia, alopecia, and cough) decreased significantly at twelve months (50% vs. 30.9%, 29.4% vs. 13.2%, and 23.5% vs. 7.4%; respectively, p = 0.007); in contrast, other persistent symptoms (sleep-wake and memory disorders) were more frequent (5.9% vs. 32.4% and 4.4% vs. 20.6%; respectively, p = ≤0.001). Regarding QoL, a statistically significant improvement was observed in some scores over time, p = ≤0.037. At twelve months, dyspnea, myalgia, and depression were risk factors associated with a poor physical component summary (PCS), p = ≤0.027, whereas anxiety, depression, and fatigue were associated with a poor mental component summary (MCS), p = ≤0.015. Conclusion: As the proportion of persistent symptoms at twelve months is high, we suggest that patients must continue under long-term follow up to reclassify, diagnose, and treat new onset symptoms/diseases.

Omics methods are widely used in basic biology and translational medicine research. More and more omics data are collected to explain the impact of certain risk factors on clinical outcomes. To explain the mechanism of the risk factors, a core question is how to find the genes/proteins/metabolites that mediate their effects on the clinical outcome. Mediation analysis is a modeling framework to study the relationship between risk factors and pathological outcomes, via mediator variables. However, high-dimensional omics data are far more challenging than traditional data: (1) From tens of thousands of genes, can we overcome the curse of dimensionality to reliably select a set of mediators? (2) How do we ensure that the selected mediators are functionally consistent? (3) Many biological mechanisms contain nonlinear effects. How do we include nonlinear effects in the high-dimensional mediation analysis? (4) How do we consider multiple risk factors at the same time? To meet these challenges, we propose a new exploratory mediation analysis framework, medNet, which focuses on finding mediators through predictive modeling. We propose new definitions for predictive exposure, predictive mediator, and predictive network mediator, using a statistical hypothesis testing framework to identify predictive exposures and mediators. Additionally, two heuristic search algorithms are proposed to identify network mediators, essentially subnetworks in the genome-scale biological network that mediate the effects of single or multiple exposures. We applied medNet on a breast cancer data set and a metabolomics data set combined with food intake questionnaire data. It identified functionally consistent network mediators for the exposures' impact on the outcome, facilitating data interpretation., (© 2024 Cai et al.; Published by Cold Spring Harbor Laboratory Press.)

Background: Single-nucleotide polymorphisms (SNPs) in fatty acid desaturase (FADS) genes may modify dietary fatty acid requirements and influence cardiometabolic health (CMH)., Objectives: We evaluated the role of selected variants in maternal and offspring FADS genes on offspring CMH at the age of 11 y and assessed interactions of genotype with diet quality and prenatal docosahexaenoic acid (DHA) supplementation., Methods: We used data from offspring (n = 203) born to females who participated in a randomized controlled trial of DHA supplementation (400 mg/d) from midgestation to delivery. We generated a metabolic syndrome (MetS) score from body mass index, high-density lipoprotein cholesterol, triglycerides, systolic blood pressure, and fasting glucose and identified 6 distinct haplotypes from 5 offspring FADS SNPs. Dietary n-6 (ω-6):n-3 fatty acid ratios were derived from 24-h recall data (n = 141). We used generalized linear models to test associations of offspring diet and FADS haplotypes with MetS score and interactions of maternal and offspring FADS SNP rs174602 with prenatal treatment group and dietary n-6:n-3 ratio on MetS score., Results: Associations between FADS haplotypes and MetS score were null. Offspring SNP rs174602 did not modify the association of prenatal DHA supplementation with MetS score. Among children with TT or TC genotype for SNP rs174602 (n = 88), those in the highest n-6:n-3 ratio tertile (>8.61) had higher MetS score relative to the lowest tertile [<6.67) (Δ= 0.36; 95% confidence interval (CI): 0.03, 0.69]. Among children with CC genotype (n = 53), those in the highest n-6:n-3 ratio tertile had a lower MetS score relative to the lowest tertile (Δ= -0.23; 95% CI: -0.61, 0.16)., Conclusions: There was evidence of an interaction of offspring FADS SNP rs174602 with current dietary polyunsaturated fatty acid intake, but not with prenatal DHA supplementation, on MetS score. Further studies may help to determine the utility of targeted supplementation strategies and dietary recommendations based on genetic profile., (Copyright © 2024. Published by Elsevier Inc.)

Background: VISTA is a well-known immune checkpoint in T cell biology, but its role in innate immunity is less established. Here, we investigated the role of VISTA on anticancer macrophage immunity, with a focus on phagocytosis, macrophage polarization and concomitant T cell activation., Methods: Macrophages, differentiated from VISTA overexpressed THP-1 cells and cord blood CD34 + cell-derived monocytes, were used in phagocytosis assay using B lymphoma target cells opsonized with Rituximab. PBMC-derived macrophages were used to assess the correlation between phagocytosis and VISTA expression. qRT-PCR, flow cytometry, and enzyme-linked immunosorbent assay were performed to analyze the impact of VISTA on other checkpoints and M1/M2-like macrophage biology. Additionally, flow cytometry was used to assess the frequency of CD14 + monocytes expressing VISTA in PBMCs from 65 lymphoma patients and 37 healthy donors., Results: Ectopic expression of VISTA in the monocytic model cell line THP-1 or in primary monocytes triggered differentiation towards the macrophage lineage, with a marked increase in M2-like macrophage-related gene expression and decrease in M1-like macrophage-related gene expression. VISTA expression in THP-1 and monocyte-derived macrophages strongly downregulated expression of SIRPα, a prominent 'don't eat me' signal, and augmented phagocytic activity of macrophages against cancer cells. Intriguingly, expression of VISTA's extracellular domain alone sufficed to trigger phagocytosis in ∼ 50% of cell lines, with those cell lines also directly binding to recombinant human VISTA, indicating ligand-dependent and -independent mechanisms. Endogenous VISTA expression was predominantly higher in M2-like macrophages compared to M0- or M1-like macrophages, with a positive correlation observed between VISTA expression in M2c macrophages and their phagocytic activity. VISTA-expressing macrophages demonstrated a unique cytokine profile, characterized by reduced IL-1β and elevated IL-10 secretion. Furthermore, VISTA interacted with MHC-I and downregulated its surface expression, leading to diminished T cell activation. Notably, VISTA surface expression was identified in monocytes from all lymphoma patients but was less prevalent in healthy donors., Conclusions: Collectively, VISTA expression associates with and drives M2-like activation of macrophages with a high phagocytic capacity yet a decrease in antigen presentation capability to T cells. Therefore, VISTA is a negative immune checkpoint regulator in macrophage-mediated immune suppression., (© 2024. The Author(s).)

Most diseases that affect human beings across the world are now treated with drugs of organic origin. However, some of these are associated with side effects, toxicity, and resistance phenomena. For the treatment of many illnesses, the development of new molecules with pharmacological potential is now an urgent matter. The biological activities of metal complexes have been reported to have antitumor, antimicrobial, anti-inflammatory, anti-infective and antiparasitic effects, amongst others. Metal complexes are effective because they possess unique properties. For example, the complex entity possesses the effective biological activity, then the formation of coordination bonds between the metal ions and ligands is controlled, metal ions provide it with extraordinary mechanisms of action because of characteristics such as d-orbitals, oxidation states, and specific orientations; metal complexes also exhibit good stability and good physicochemical properties such as water solubility. Platinum is a transition metal widely used in the design of drugs with antineoplastic activities; however, platinum is associated with side effects which have made it necessary to search for, and design, novel complexes based on other metals. Copper is a biometal which is found in living systems; it is now used in the design of metal complexes with biological activities that have demonstrated antitumoral, antimicrobial and anti-inflammatory effects, amongst others. In this review, we consider the open horizons of Cu(II)- and Pt(II)-based complexes, new trends in their design, their synthesis, their biological activities and their targets of action.

Individuals with cystic fibrosis (CF) have dysfunctional intestinal microbiota and increased gastrointestinal (GI) inflammation also known as GI dysbiosis. It is hypothesized that administration of high-dose cholecalciferol (vitamin D 3 ) together with a prebiotic (inulin) will be effective, and possibly additive or synergistic, in reducing CF-related GI and airway dysbiosis. Thus, a 2 x 2 factorial design, placebo-controlled, double-blinded, pilot and feasibility, clinical trial was proposed to test this hypothesis. Forty adult participants with CF were block-randomized into one of four groups: 1) high-dose oral vitamin D 3 (50,000 IU weekly) plus oral prebiotic placebo daily; 2) oral prebiotic (12 g inulin daily) plus oral placebo vitamin D 3 weekly; 3) combined oral vitamin D 3 weekly and oral prebiotic inulin daily; and 4) oral vitamin D 3 placebo weekly and oral prebiotic placebo. The primary endpoints included 12-week changes in the microbial bacterial communities, gut and airway microbiota richness and diversity before and after the intervention. This pilot study examined whether vitamin D 3 with or without prebiotics supplementation was feasible, changed airway and gut microbiota, and reduced dysbiosis, which in turn, may improve health outcomes and quality of life of patients with CF., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.