The Puerto Rican Infant Metagenomic and Epidemiologic Study of Respiratory Outcomes (PRIMERO): Design and Baseline Characteristics for a Birth Cohort Study of Early-life Viral Respiratory Illnesses and Airway Dysfunction in Puerto Rican Children.

Epidemiologic studies demonstrate an association between early-life respiratory illnesses (RIs) and the development of childhood asthma. However, it remains uncertain whether these children are predisposed to both conditions or if early-life RIs induce alterations in airway function, immune responses, or other human biology that contribute to the development of asthma. Puerto Rican children experience a disproportionate burden of early-life RIs and asthma, making them an important population for investigating this complex interplay. PRIMERO, the Puerto Rican Infant Metagenomics and Epidemiologic Study of Respiratory Outcomes , recruited pregnant women and their newborns to investigate how the airways develop in early life among infants exposed to different viral RIs, and will thus provide a critical understanding of childhood asthma development. As the first asthma birth cohort in Puerto Rico, PRIMERO will prospectively follow 2,100 term healthy infants. Collected samples include post-term maternal peripheral blood, infant cord blood, the child's peripheral blood at the year two visit, and the child's nasal airway epithelium, collected using minimally invasive nasal swabs, at birth, during RIs over the first two years of life, and at annual healthy visits until age five. Herein, we describe the study's design, population, recruitment strategy, study visits and procedures, and primary outcomes.

Virtual Reality Breathing Interventions for Mental Health: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Breathing exercises have been shown to reduce mental health problems among clinical and non-clinical populations. Although virtual reality (VR) breathing interventions are assumed to have potential benefits, it remains unclear whether VR breathing interventions are more effective at improving mental health than non-VR breathing interventions. We conducted a systematic literature search in six electronic databases (Web of Science, PsycINFO, Embase, Cochrane Central Register of Controlled Trials, Scopus, and PubMed) from inception to 30th September, 2022. We included randomized controlled trials in adults evaluating effects of VR compared to non-VR breathing interventions on primary outcomes of mental health (stress, anxiety and mood), and secondary outcomes of physiological stress measures (e.g., heart rate (HR), heart rate variability (HRV)). Within these selected studies, we explored differences in likeability and future use between VR and non-VR breathing interventions. 2.848 records were identified of which 65 full-text articles were assessed. Six RCTs were included, of which five were suitable for meta-analyses. Comparing VR to non-VR breathing interventions, there were no significant differences in overall mental health, stress, anxiety or mood, nor in HR or HRV. There was no evidence that participants liked VR breathing interventions more than non-VR, nor would use them more in the future. These results suggest that there is no evidence that VR breathing interventions are more effective than non-VR in improving mental health outcomes, HR, HRV. Further research is required to determine whether there may be advantages to longer-term VR-implementation and practice, and explore possible mechanisms.

Stream food webs in tropical mountains rely on allochthonous carbon regardless of land use.

The relative importance of allochthonous and autochthonous carbon (C) as sources of energy for tropical stream food webs remains an open question. Allochthonous C might be the main energy source for small and shaded forest streams, while autochthonous C is more likely to fuel food webs draining land uses with less dense vegetation. We studied food webs in cloud forest streams draining watersheds with forests, coffee plantations, and pastures. Our goal was to assess the effects of those land uses on the C source and structure of stream food webs. The study took place in tropical montane streams in La Antigua Watershed, in eastern Mexico. We selected three streams per land use and sampled biofilm and leaf litter as the main food resources, and macroinvertebrates and aquatic vertebrates from different trophic guilds. Samples were analyzed for δ13C and δ15N isotopes. Using a Bayesian mixing model, we estimated the proportional assimilation of autochthonous and allochthonous carbon by each guild. We found that consumers were mostly using allochthonous C in all streams, regardless of watershed land use. Our findings indicate that montane cloud forest streams are dominated by allochthony even in watersheds dominated by pastures. Abundant precipitation in this life zone might facilitate the movement of allochthonous C into streams. While food webs of streams from coffee plantations and pastures also rely on allochthonous resources, other impacts do result in important changes in stream functioning.

Establishing a baseline of antibiotic use in Massachusetts jails reveals heterogeneity in quantity of prescriptions and duration of therapy.

Optimizing antibiotic prescribing is a crucial element of the fight against antibiotic resistance. Antibiotic prescribing patterns in jails have not been studied. We established a baseline of antibiotic prescribing between Massachusetts jails. We detected heterogeneity in quantity and duration of antibiotic prescriptions, revealing an opportunity for improved practice.

Land use scenarios, seasonality, and stream identity determine the water physicochemistry of tropical cloud forest streams.

Background: Land use is a major factor determining stream water physicochemistry. However, most streams move from one land use type to another as they drain their watersheds. Here, we studied three land use scenarios in a tropical cloud forest zone in Mexico. We addressed three main goals, to: (1) assess how land use scenarios generate different patterns in stream physicochemical characteristics; (2) explore how seasonality (i.e., dry, dry-to-wet transition, and wet seasons) might result in changes to those patterns over the year; and (3) explore whether physicochemical patterns in different scenarios resulted in effects on biotic components (e.g., algal biomass). Methods: We studied Tropical Mountain Cloud Forest streams in La Antigua watershed, Mexico. Streams drained different three scenarios, streams with (1) an upstream section draining forest followed by a pasture section (F-P), (2) an upstream section in pasture followed by a forest section (P-F), and (3) an upstream forest section followed by coffee plantation (F-C). Physicochemistry was determined at the upstream and downstream sections, and at the boundary between land uses. Measurements were seasonal, including temperature, dissolved oxygen, conductivity, and pH. Water was analyzed for suspended solids, alkalinity, silica, chloride, sulfate, magnesium, sodium, and potassium. Nutrients included ammonium, nitrate, and phosphorus. We measured benthic and suspended organic matter and chlorophyll. Results: Streams presented strong seasonality, with the highest discharge and suspended solids during the wet season. Scenarios and streams within each scenario had distinct physicochemical signatures. All three streams within each scenario clustered together in ordination space and remained close to each other during all seasons. There were significant scenario-season interactions on conductivity (F = 9.5, P < 0.001), discharge (F = 56.7, P < 0.001), pH (F = 4.5, P = 0.011), Cl- (F = 12.2, P < 0.001), SO42- (F = 8.8, P < 0.001) and NH4+ (F = 5.4, P = 0.005). Patterns within individual scenarios were associated with stream identity instead of land use. Both P-F and F-C scenarios had significantly different physicochemical patterns from those in F-P in all seasons (Procrustes analysis, m12 = 0.05-0.25; R = 0.86-0.97; P < 0.05). Chlorophyll was significantly different among scenarios and seasons (F = 5.36, P = 0.015, F = 3.81, P = 0.42, respectively). Concentrations were related to physicochemical variables more strongly during the transition season. Conclusion: Overall, land use scenarios resulted in distinctive water physicochemical signatures highlighting the complex effects that anthropogenic activities have on tropical cloud forest streams. Studies assessing the effect of land use on tropical streams will benefit from assessing scenarios, rather than focusing on individual land use types. We also found evidence of the importance that forest fragments play in maintaining or restoring stream water physicochemistry.

An unusual outbreak of dermatitis due to rodent mite infestation in an acute-care hospital.

We report an outbreak of dermatitis associated with Ornithonysus bacoti and Liponyssoides sanguineus infestation in an acute ambulatory care setting. Healthcare workers developed dermatitis prior to the identification of the outbreak. A collaborative team effort resulted in complete eradication.

EIF4A inhibition targets bioenergetic homeostasis in AML MOLM-14 cells in vitro and in vivo and synergizes with cytarabine and venetoclax.

BACKGROUND: Acute myeloid leukemia (AML) is an aggressive hematological cancer resulting from uncontrolled proliferation of differentiation-blocked myeloid cells. Seventy percent of AML patients are currently not cured with available treatments, highlighting the need of novel therapeutic strategies. A promising target in AML is the mammalian target of rapamycin complex 1 (mTORC1). Clinical inhibition of mTORC1 is limited by its reactivation through compensatory and regulatory feedback loops. Here, we explored a strategy to curtail these drawbacks through inhibition of an important effector of the mTORC1signaling pathway, the eukaryotic initiation factor 4A (eIF4A). METHODS: We tested the anti-leukemic effect of a potent and specific eIF4A inhibitor (eIF4Ai), CR-1-31-B, in combination with cytosine arabinoside (araC) or the BCL2 inhibitor venetoclax. We utilized the MOLM-14 human AML cell line to model chemoresistant disease both in vitro and in vivo. In eIF4Ai-treated cells, we assessed for changes in survival, apoptotic priming, de novo protein synthesis, targeted intracellular metabolite content, bioenergetic profile, mitochondrial reactive oxygen species (mtROS) and mitochondrial membrane potential (MMP). RESULTS: eIF4Ai exhibits anti-leukemia activity in vivo while sparing non-malignant myeloid cells. In vitro, eIF4Ai synergizes with two therapeutic agents in AML, araC and venetoclax. EIF4Ai reduces mitochondrial membrane potential (MMP) and the rate of ATP synthesis from mitochondrial respiration and glycolysis. Furthermore, eIF4i enhanced apoptotic priming while reducing the expression levels of the antiapoptotic factors BCL2, BCL-XL and MCL1. Concomitantly, eIF4Ai decreases intracellular levels of specific metabolic intermediates of the tricarboxylic acid cycle (TCA cycle) and glucose metabolism, while enhancing mtROS. In vitro redox stress contributes to eIF4Ai cytotoxicity, as treatment with a ROS scavenger partially rescued the viability of eIF4A inhibition. CONCLUSIONS: We discovered that chemoresistant MOLM-14 cells rely on eIF4A-dependent cap translation for survival in vitro and in vivo. EIF4A drives an intrinsic metabolic program sustaining bioenergetic and redox homeostasis and regulates the expression of anti-apoptotic proteins. Overall, our work suggests that eIF4A-dependent cap translation contributes to adaptive processes involved in resistance to relevant therapeutic agents in AML.

Warmer Temperature and Spatiotemporal Dynamics during Primary Succession on Tropical Coastal Dunes.

Coastal dunes are sensitive indicators of climate change: it is expected that higher precipitation and warmer temperature will promote vegetation growth and sand stabilization. Alternatively, dunes may become active during severe droughts, which would reduce plant cover and increase sand mobility. Consequently, it is relevant to explore community shifts and self-organization processes to better understand how coastal dunes vegetation will respond to these projected changes. Primary succession allows the exploration of community assembly and reorganization processes. We focused on three environmental variables (bare sand, temperature, and precipitation) and five successional groups (facilitators, colonizers, sand binders, nucleators, and competitors). For 25 years (from 1991 to 2016), species turnover was monitored in 150 permanent plots (4 × 4 m) placed on an initially mobile dune system located on the coast of the Gulf of Mexico. The spatiotemporal dynamics observed during primary succession were consistent with the facilitation nucleation model. As late colonizers grew and expanded, psammophytes became locally extinct. The spatial patterns revealed that ecological succession did not occur evenly on the dunes. In addition, the increased mean yearly temperature during the last decades seemed to be associated with the accelerated increment in plant cover and species richness, which had not been registered before in Mexico.

A cross-sectional study of free-roaming dogs in a Patagonian city: Their distribution and intestinal helminths in relation to socioeconomic aspects of neighborhoods.

Human and dog health are inextricably linked, and although our relationship with dogs brings numerous benefits for our well-being, it is known that they can transmit disease. Bariloche is a Patagonian tourist city with heterogeneous social composition. This cross-sectional study evaluates the population of free-roaming dogs and their intestinal parasites in relation to the socioeconomic level of the city's human population. Census areas were used as survey units, stratified in three levels according to socioeconomic status. The free-roaming dog population was estimated by walking around each census area. Eight fresh feces per census count area were collected and analyzed using coproparasitological flotation tests, and CoproELISA was used to detect Echinococcus sp. A total of 858 free-roaming dogs were registered along 40.9 km, with significant differences between socioeconomic strata: the highest numbers were found in the lowest income strata. Of the feces collected, 39.2% tested positive for parasites, those associated with a lower socioeconomic level having higher percentages of positive feces and a greater number of species. Eight species of helminths were found, some of which were zoonotic, such as Echinococcus sp., Toxocara canis, and Dibothriocephalus latus. The presence of parasites can be explained by the number of free-roaming dogs per census count area. The free-roaming dogs generally have owners, and their parasitic infection is strongly associated with the socioeconomic level of the population. The main problem is irresponsible pet care, which generates healthy conditions for both dogs and humans. Thus, both dogs and humans deserve effective ethical public policies.

Primary Care Population Management for COVID-19 Patients.

BACKGROUND: Most patients infected with SARS-CoV-2 have mild to moderate symptoms manageable at home; however, up to 20% develop severe illness requiring additional support. Primary care practices performing population management can use these tools to remotely assess and manage COVID-19 patients and identify those needing additional medical support before becoming critically ill. AIM: We developed an innovative population management approach for managing COVID-19 patients remotely. SETTING: Development, implementation, and evaluation took place in April 2020 within a large urban academic medical center primary care practice. PARTICIPANTS: Our panel consists of 40,000 patients. By April 27, 2020, 305 had tested positive for SARS-CoV-2 by RT-qPCR. Outreach was performed by teams of doctors, nurse practitioners, physician assistants, and nurses. PROGRAM DESCRIPTION: Our innovation includes an algorithm, an EMR component, and a twice daily population report for managing COVID-19 patients remotely. PROGRAM EVALUATION: Of the 305 patients with COVID-19 in our practice at time of submission, 196 had returned to baseline; 54 were admitted to hospitals, six of these died, and 40 were discharged. DISCUSSION: Our population management strategy helped us optimize at-home care for our COVID-19 patients and enabled us to identify those who require inpatient medical care in a timely fashion.

The effect of respiratory viral assay panel on antibiotic prescription patterns at discharge in adults admitted with mild to moderate acute exacerbation of COPD: a retrospective before- after study.

BACKGROUND: Despite well-defined criteria for use of antibiotics in patients presenting with mild to moderate Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD), their overuse is widespread. We hypothesized that following implementation of a molecular multiplex respiratory viral panel (RVP), AECOPD patients with viral infections would be more easily identified, limiting antibiotic use in this population. The primary objective of our study was to investigate if availability of the RVP decreased antibiotic prescription at discharge among patients with AECOPD. METHODS: This is a single center, retrospective, before (pre-RVP) - after (post-RVP) study of patients admitted to a tertiary medical center from January 2013 to March 2016. The primary outcome was antibiotic prescription at discharge. Groups were compared using univariable and multivariable logistic-regression. RESULTS: A total of 232 patient-episodes were identified, 133 following RVP introduction. Mean age was 68.1 (pre-RVP) and 68.3 (post-RVP) years respectively (p = 0.88). Patients in pre-RVP group were similar to the post-RVP group with respect to gender (p = 0.54), proportion of patients with BMI < 21(p = 0.23), positive smoking status (p = 0.19) and diagnoses of obstructive sleep apnea (OSA, p = 0.16). We found a significant reduction in antibiotic prescription rate at discharge in patients admitted with AECOPD after introduction of the respiratory viral assay (pre-RVP 77.8% vs. post-RVP 63.2%, p = 0.01). In adjusted analyses, patients in the pre-RVP group [OR 2.11 (CI: 1.13-3.96), p = 0.019] with positive gram stain in sputum [OR 4.02 (CI: 1.61-10.06), p = 0.003] had the highest odds of antibiotic prescription at discharge. CONCLUSIONS: In patients presenting with mild to moderate Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD), utilization of a comprehensive respiratory viral panel can significantly decrease the rate of antibiotic prescription at discharge.

Magnesium-sensitive upstream ORF controls PRL phosphatase expression to mediate energy metabolism.

Phosphatases of regenerating liver (PRL-1, PRL-2, and PRL-3, also known as PTP4A1, PTP4A2, and PTP4A3) control magnesium homeostasis through an association with the CNNM magnesium transport regulators. Although high PRL levels have been linked to cancer progression, regulation of their expression is poorly understood. Here we show that modulating intracellular magnesium levels correlates with a rapid change of PRL expression by a mechanism involving its 5'UTR mRNA region. Mutations or CRISPR-Cas9 targeting of the conserved upstream ORF present in the mRNA leader derepress PRL protein synthesis and attenuate the translational response to magnesium levels. Mechanistically, magnesium depletion reduces intracellular ATP but up-regulates PRL protein expression via activation of the AMPK/mTORC2 pathway, which controls cellular energy status. Hence, altered PRL-2 expression leads to metabolic reprogramming of the cells. These findings uncover a magnesium-sensitive mechanism controlling PRL expression, which plays a role in cellular bioenergetics.

Metabolic rewiring beyond Warburg in chronic lymphocytic leukemia: How much do we actually know?

Chronic Lymphocytic Leukemia (CLL) is the most common adult leukemia in the western world. CLL consists of the accumulation of malignant B-cells in the blood stream and homing tissues. Although treatable, this disease is not curable, and resistance or relapse is often present. In many cancers, the study of metabolic reprograming has uncovered novel targets that are already being exploited in the clinic. However, CLL metabolism is still poorly understood. The ability of CLL lymphocytes to adapt to diverse microenvironments is accompanied by modifications in cell metabolism, revealing the challenge of targeting the CLL lymphocytes present in all different compartments. Despite this, the study of CLL metabolism led to an ongoing clinical trial using glucose uptake and mitochondrial respiration inhibitors. In contrast, glutamine and fatty acid metabolism remain to be further exploited in CLL. Here, we summarize the present knowledge of CLL metabolism, as well as the metabolic influence of Myc, ATM and p53 on CLL lymphocytes.

Microbial Identification Using DNA Target Amplification and Sequencing: Clinical Utility and Impact on Patient Management.

Broad-range polymerase chain reaction (PCR) is increasingly used in patients with culture-negative infections; however, few studies have assessed the diagnostic utility of this test in this context. We performed a retrospective cohort study of patients who had clinical specimens sent for broad-range PCR, aiming to evaluate performance and determine impact on patient management. Organisms were identified in 21/71 samples. High numbers of polymorphonuclear leukocytes on Gram stain (odds ratio [OR], 4.17; P = .04) and acute inflammation on histopathology (OR, 5.69; P = .02) were significantly associated with a positive result. Management was altered in 18 patients, 11 with positive and 7 with negative results. Overall, broad-range PCR assay had the highest impact in patients with microscopic evidence of inflammation. Physicians ordering this complex, difficult to interpret, and expensive test should carefully consider all available clinical information on an individualized basis to optimize its performance.

Ibrutinib Resistance Is Reduced by an Inhibitor of Fatty Acid Oxidation in Primary CLL Lymphocytes.

Chronic Lymphocytic Leukemia (CLL) is an incurable disease, characterized by the accumulation of malignant B-lymphocytes in the blood stream (quiescent state) and homing tissues (where they can proliferate). In CLL, the targeting of B-cell receptor signaling through a Burton's tyrosine kinase inhibitor (ibrutinib) has rendered outstanding clinical results. However, complete remission is not guaranteed due to drug resistance or relapse, revealing the need for novel approaches for CLL treatment. The characterization of metabolic rewiring in proliferative cancer cells is already being applied for diagnostic and therapeutic purposes, but our knowledge of quiescent cell metabolism-relevant for CLL cells-is still fragmentary. Recently, we reported that glutamine metabolism in primary CLL cells bearing the del11q deletion is different from their del11q negative counterparts, making del11q cells especially sensitive to glutaminase and glycolysis inhibitors. In this work, we used our primary CLL lymphocyte bank and compounds interfering with central carbon metabolism to define metabolic traits associated with ibrutinib resistance. We observe a differential basal metabolite uptake linked to ibrutinib resistance, favoring glutamine uptake and catabolism. Upon ibrutinib treatment, the redox balance in ibrutinib resistant cells is shifted toward NADPH accumulation, without an increase in glutamine uptake, suggesting alternative metabolic rewiring such as the activation of fatty acid oxidation. In accordance to this idea, the curtailing of fatty acid oxidation by CPT1 inhibition (etomoxir) re-sensitized resistant cells to ibrutinib. Our results suggest that fatty acid oxidation could be explored as a target to overcome ibrutinib resistance.

eIF4A inhibition prevents the onset of cytokine-induced muscle wasting by blocking the STAT3 and iNOS pathways.

Cachexia is a deadly muscle wasting syndrome that arises under conditions linked to chronic inflammation, such as cancer. Cytokines, including interferon γ (IFNγ), tumor necrosis factor α (TNFα) and interleukin-6 (IL-6), and their downstream effectors such as Signal Transducer and Activator of Transcription 3 (STAT3), have been shown to play a prominent role in muscle wasting. Previously, we demonstrated that Pateamine A (PatA), a compound that targets eukaryotic initiation factor 4A (eIF4A), could prevent muscle wasting by modulating the translation of the inducible Nitric Oxide Synthase (iNOS) mRNA. Here we show that hippuristanol, a compound that impedes eIF4A in a manner distinct from PatA, similarly inhibits the iNOS/NO pathway and cytokine-induced muscle wasting. Furthermore, we show that hippuristanol perturbs the activation of the STAT3 pathway and expression of STAT3-gene targets such as IL-6. The decreased activation of STAT3, which resulted from a decrease in STAT3 protein expression, was due to the inhibition of STAT3 translation as there were no changes in STAT3 mRNA levels. These effects are likely dependent on the inhibition of eIF4A activity since we observed similar results using PatA. Our results identify the inhibition of eIF4A-responsive transcripts, such as STAT3, as a viable approach to alleviate cachexia.

[Responsible ownership of dogs and human health in neighborhoods of San Carlos de Bariloche, Argentina]. / Tenencia responsable de perros y salud humana en barrios de San Carlos de Bariloche, Argentina.

Human relationship with dogs associates with numerous and varied benefits on human health; however, it also presents significant risks. The goal of this study was to describe demographic parameters and characteristics of dog ownership with possible implications on human health and to evaluate the prevalence of dog bites and traffic accidents due to dogs. Interviews were conducted in the neighborhoods of Nuestras Malvinas and Nahuel Hue in San Carlos de Bariloche. The percentage of homes with at least one dog, the average number of dogs per home, the prevalence of dog bites and traffic accidents due to dogs and the general awareness of the population on dog transmitted zoonoses were estimated. Regarding ownership characteristics, the degree of sterilization, vaccination and parasite control and the percentage of dogs allowed to roam freely in public places were evaluated. A total of 141 interviews were conducted; 87% of the households had at least one dog, with an average of 2.2 dogs. In 26% of the households someone had suffered a traffic accident caused by dogs and in 41% someone had been bitten. Antiparasite treatment was administered to 83% of the dogs in the last 12 months, on average 1.4 times (recommended 6 times), 51% were sterilized, 55% were allowed to roam freely. This study shows a disturbing situation regarding the canine population of the evaluated neighborhoods. The number of dogs allowed to roam freely and the low level of parasite control and sterilization provide suitable conditions for the spread of zoonoses.