Advancing Multicomponent Strategies to Macrobicyclic Peptides.

Macrocyclization of peptides is typically used to fix specific bioactive conformations and improve their pharmacological properties. Recently, macrobicyclic peptides have received special attention owing to their capacity to mimic protein structures or be key components of peptide-drug conjugates. Here, we describe the development of novel synthetic strategies for two distinctive types of peptide macrobicycles. A multicomponent macrocyclo-dimerization approach is introduced for the production of interconnected ß-turns, allowing two macrocyclic rings to be formed and dimerized in one pot. Also, an on-resin double stapling strategy is described for the assembly of lactam-bridged macrobicycles with stable tertiary folds.

N-Acetylcistein for thrombotic thrombocytopenic purpura: an observational case series study.

Acquired thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder. N-Acetylcysteine (NAC) rapidly degrades ultra-large von Willebrand factor multimers by disrupting the disulfide bonds. We report a series of twelve consecutive patients diagnosed with acquired TTP successfully treated with high-dose NAC (150 mg/kg/day) in combination with plasma exchange and steroids. Eight patients also received rituximab. Two patients presented refractory TTP. All patients achieved a quick clinical response in a median time of 5.5 days after starting NAC and are alive after a median follow-up of 29 months. The treatment was feasible and well tolerated. These data provide further evidence of the potential benefit and safety of adding NAC to the standard of care.

The poor prognosis of low hypodiploidy in adults with B-cell precursor acute lymphoblastic leukaemia is restricted to older adults and elderly patients.

The prognostic significance of low-hypodiploidy has not been extensively evaluated in minimal residual disease (MRD)-oriented protocols for adult acute lymphoblastic leukaemia (ALL). We analysed the outcome of hypodiploid adult ALL patients treated within Programa Español de Tratamientos en Hematología (PETHEMA) protocols. The 5-year cumulative incidence of relapse (CIR) of low-hypodiploid B-cell precursor (BCP)-ALL was significantly higher than that of high-hypodiploids (52% vs. 12%, P = 0.013). Low-hypodiploid BCP-ALL patients aged ≤35 years showed superior survival (71% vs. 21%, P = 0.026) and lower 5-year CIR (17% vs. 66%, P = 0.090) than low-hypodiploids aged >35 years. Older adults and elderly low-hypodiploid BCP-ALL patients show dismal prognosis although achieving an end-induction good MRD response.

Confirmatory factor analysis of the Spanish version of the revised memory and behavior problems checklist.

BACKGROUND: Behavioral and psychological symptoms of Dementia (BPSD) are a cause of significant stress in caregivers. The revised memory and behavior problems checklist (RMBPC) (Teri et al., 1992) is an instrument used for the assessment of BPSD. The psychometric properties of the RMBPC-Spanish version were analyzed. METHOD: 361 family caregivers of people with dementia were interviewed individually. The RMBPC is a 24-item questionnaire that assesses both the frequency of the BPSD and the reaction they cause in the caregiver. It has three factors: memory problems, disruptive behaviors, and depressive behaviors. Caregivers' depressive symptomatology, anxiety and burden, and the functional capacity of the person with dementia were also measured. RESULTS: The results of a confirmatory factor analysis (CFA) show that the original three-factor model with 24 items, with error covariances, had a marginally acceptable adjustment for the frequency and reaction scales. The deletion of items with low factor loadings results in a better adjustment of the data to the model, for both the frequency and reaction scales. We found adequate internal consistency for all subscales, and significant associations between the subscales, burden, anxiety, and depression. CONCLUSIONS: The results suggest that the Spanish version of the RMBPC shows adequate adjustment for the three-factor model with 24-items, but that removing some of the items improves the adjustment. The results support the use of this instrument for the assessment of BPSD in Spanish people with dementia.

Behavioral correlates of anxiety in well-functioning older adults.

BACKGROUND: Research on the behavioral correlates of anxiety in older adults is sparse. The aim of this study was to explore the association of anxiety with behavioral patterns defined by health, activity, emotional and social variables. METHODS: A convenience sample of 395 older adults completed measures of health, activity, emotions, social variables and experiential avoidance. Cross-sectional data were analysed using cluster analysis. RESULTS: Five clusters were identified: active healthy, healthy, active vulnerable, lonely inactive and frail lonely. Participants in the active healthy and healthy clusters showed the highest scores on health variables (vitality and physical function), and adaptive scores on the rest of variables. They also reported the lowest scores on anxiety and included the lowest number of cases with clinically significant anxiety levels. Active vulnerable showed high scores on social support, leisure activities and capitalization on them but low scores in vitality and physical functioning. Participants in the lonely inactive cluster reported the highest mean score in experiential avoidance and high scores on boredom and loneliness, and low scores on social support, leisure activities capitalizing on pleasant activities and health variables. Frail lonely represent a particularly vulnerable profile of participants, similar to that of lonely inactive, but with significantly lower scores on health variables and higher scores on boredom and hours watching TV. CONCLUSIONS: Anxiety in older adults is not only linked to poor health, but also to dysfunctional social behavior, loneliness, boredom and experiential avoidance. Maladaptive profiles of older adults with regard to these variables have been identified.

Efficacy of diltiazem 2% rectal gel in the treatment of chronic anal fissure: a retrospective observational study.

OBJECTIVE: The aim of this study is to describe the effectiveness and safety of a magistral formulation of diltiazem 2% rectal gel as a treatment for chronic anal fissure. MATERIAL AND METHODS: A retrospective observational study of all patients that began treatment with diltiazem 2% gel during 2019. The primary endpoint of the study was anal fissure healing. We also looked for differences in effectiveness between those initiating treatment and those who had been previously treated, long-term effectiveness through a 2-year follow-up and frequency of adverse effects. RESULTS: Of the 166 patients included in the study, anal fissure healed in 72.9%. We detected adverse effects in 12 patients, the most common was local irritation. After 2 years of follow-up, 88% of patients did not relapse. CONCLUSION: In this study, use of topical diltiazem 2% has been shown to be effective and safe in the treatment of anal fissure and should be considered as the first line of therapy.

OBJETIVO: El objetivo de este estudio es describir la efectividad y la seguridad de una fórmula magistral de diltiazem 2% gel rectal, como tratamiento de la fisura anal crónica. MATERIAL Y MÉTODOS: Un studio observacional retrospectivo de todos los pacientes que comenzaron a ser tratados con diltiazem 2% gel durante el año 2019. La variable principal del estudio fue la cicatrización de la fisura anal. También se buscaron diferencias de efectividad entre aquellos que iniciaban el tratamiento y los que ya habían sido tratados previamente, efectividad a largo plazo mediante un seguimiento de 2 años y frecuencia de aparición de efectos adversos. RESULTADOS: De los 166 pacientes incluidos en el estudio, el 72,9% cicatrizaron la fisura anal. No detectamos diferencias estadísticamente significativas de efectividad entre los pacientes naive y aquellos que ya habían sido tratados. Detectamos efectos adversos en 12 pacientes, siendo el más frecuente la irritación local. Tras 2 años de seguimiento, el 88% de los pacientes no presentaron ninguna recaída. CONCLUSIÓN: En este estudio, el uso de diltiazem 2% tópico ha mostrado ser efectivo y seguro en el tratamiento de la fisura anal y debería considerarse como primera línea terapéutica.

Prediction of Klebsiella phage-host specificity at the strain level.

Phages are increasingly considered promising alternatives to target drug-resistant bacterial pathogens. However, their often-narrow host range can make it challenging to find matching phages against bacteria of interest. Current computational tools do not accurately predict interactions at the strain level in a way that is relevant and properly evaluated for practical use. We present PhageHostLearn, a machine learning system that predicts strain-level interactions between receptor-binding proteins and bacterial receptors for Klebsiella phage-bacteria pairs. We evaluate this system both in silico and in the laboratory, in the clinically relevant setting of finding matching phages against bacterial strains. PhageHostLearn reaches a cross-validated ROC AUC of up to 81.8% in silico and maintains this performance in laboratory validation. Our approach provides a framework for developing and evaluating phage-host prediction methods that are useful in practice, which we believe to be a meaningful contribution to the machine-learning-guided development of phage therapeutics and diagnostics.

Response of water yield to silvicultural treatments in a temperate forest in northern Mexico.

Forest management modifies tree cover, directly influencing various ecosystem services, such as water regulation. Evapotranspiration, water interception, surface runoff, stemflow, and throughfall are among those processes that depend on tree cover. The objective of this study was to evaluate the changes in water yield, defined as the difference between precipitation and evapotranspiration, after the application of silvicultural treatments in a temperate forest ecosystem in northern Mexico. Fifteen experimental plots were established in which the following treatments were applied: intensive management (clearcutting), semi-intensive management (selection, tree cutting of 59-61% of basal area), conservative management (selection, tree cutting of 29-31% of basal area), and no treatment (control group). Incident precipitation, throughfall, stemflow, net precipitation, interception, and surface runoff were analyzed. Results show that conservative management treatments increase water yield between 2 to 3.6 mm per m-2 ha-1 of tree basal area removed. Water flow distribution, in relation to the incident precipitation, ranged from 72.3 to 91.8% for throughfall, 0.2 to 0.4% for stemflow, 72.7 to 91.8% for net precipitation, 8.19 to 27.42% for interception or evaporation, and 0.54 to 1.93% for surface runoff. The conservative management treatment was the most viable alternative for increasing water yield without compromising timber harvesting and loss of soil due to hydric erosion.

New insights into cancer: MDM2 binds to the citrullinating enzyme PADI4.

PADI4 is one of the human isoforms of a family of enzymes implicated in the conversion of arginine to citrulline. MDM2 is an E3 ubiquitin ligase which is crucial for down-regulation of degradation of the tumor suppressor gene p53. Given the relationship between both PADI4 and MDM2 with p53-signaling pathways, we hypothesized they may interact directly, and this interaction could be relevant in the context of cancer. Here, we showed their association in the nucleus and cytosol in several cancer cell lines. Furthermore, binding was hampered in the presence of GSK484, an enzymatic PADI4 inhibitor, suggesting that MDM2 could bind to the active site of PADI4, as confirmed by in silico experiments. In vitro and in silico studies showed that the isolated N-terminal region of MDM2, N-MDM2, interacted with PADI4, and residues Thr26, Val28, Phe91 and Lys98 were more affected by the presence of the enzyme. Moreover, the dissociation constant between N-MDM2 and PADI4 was comparable to the IC50 of GSK484 from in cellulo experiments. The interaction between MDM2 and PADI4 might imply MDM2 citrullination, with potential therapeutic relevance for improving cancer treatment, due to the generation of new antigens.

Cost of care for asylum seekers and refugees entering the United States: The case of volunteer medical providers in El Paso, Texas.

BACKGROUND: Between October 2018, and February 2020, the United States saw an unprecedented increase in the number of asylum seekers and refugees arriving unexpectedly at international crossings along the US-Mexico Border. Many of these migrants needed proper medical attention, and consequently created significant pressure on local health systems. In El Paso, Texas, volunteer clinicians, collaborating closely with religious organizations and non-governmental organizations, provided outpatient medical care for the new arrivals; the county hospital provided in-patient care at local tax payers' expense. The objective of this study was to estimate costs of healthcare services offered by these volunteers in order to formulate sustainable and appropriate healthcare policies to address the needs of refugees and asylum seekers in the United States. METHODS: A mixed methods approach was used including personal interviews with stakeholders, and follow up surveys with volunteer clinicians. The cost analysis was done from the payer perspective using Medicaid reimbursement rates. RESULTS: Total costs of care provided to asylum seekers and refugees varied between $1.9MM to $4.4MM during the study period. The number of patient visits was estimated at 15,736 to 19,236, and cost per patient ranged between $99 and $281. Most common conditions treated by volunteer providers were abdominal pain, dermatological conditions, headaches, dehydration and hypertension. CONCLUSIONS: This is the first study looking at the cost of healthcare for refugees and asylum seekers provided by volunteer clinicians, in a binational context. The resources invested by volunteer providers were significant, and essential to meet medical needs of migrant populations. Without appropriate financial support, a strategy relying on volunteer and local community resources will prove unsustainable in the long term. Findings from this study will help formulate federal and local policies to support local health systems along the US-Mexico Border in providing care to future migrations into the United States.

Analysis of the Influence of Thickness and Density on Acoustic Absorption of Materials Made from Used Cigarette Butts.

The effects of the density and thickness of samples made from used cigarette butts on acoustic characteristics were analyzed in this study. All the analyzed samples showed high acoustic performance, indicating that the fabrication of acoustic absorbing material may be a good use for this problematic waste (due to its toxicity, continuous generation, lack of recycling method, etc.). An increase in either density or thickness shifted the absorption characteristics of the samples to lower frequencies and increased the overall absorption. The relationships of the frequency and value of the maximum absorption coefficient with thickness and/or density were analyzed. The shift of the maximum absorption coefficient value due to varying thickness is in good agreement with previous studies.

Initial Conditioning of Used Cigarette Filters for Their Recycling as Acoustical Absorber Materials.

Used cigarette butts represent a major and problematic form of waste, due to their abundance, toxicity, and durability. Moreover, the few proposals for their recycling are clearly insufficient, and new ones are welcome. For a new proposal regarding the reuse of used cigarette butts as acoustical absorbers in building construction, previous conditioning of the used butts is performed. This conditioning includes the elimination of moisture and toxic products accumulated in the filter of the cigarettes. Thus, in this work, the moisture content effect in acoustical absorption was analyzed, and a proposal for elimination is made. Moreover, a chemical cleaning procedure is proposed, and its influence on the acoustical behavior of the samples was also analyzed.

Phage Therapy in Livestock and Companion Animals.

The irrational use of antibiotics has led to a high emergence of multi-drug resistant (MDR) bacteria. The traditional overuse of antibiotics in the animal feed industry plays a crucial role in the emergence of these pathogens that pose both economic and health problems. In addition, antibiotics have also recently experienced an increase to treat companion animal infections, promoting the emergence of MDR bacteria in pets, which can reach humans. Phages have been proposed as an alternative for antibiotics for the treatment of livestock and companion animal infections due to their multiple advantages as adaptative drugs, such as their ability to evolve, to multiply at the site of infections, and their high specificity. Moreover, phage-derived enzymes may also be an interesting approach. However, the lack of regulation for this type of pharmaceutical hinders its potential commercialization. In this review, we summarize the main recent studies on phage therapy in livestock and companion animals, providing an insight into current advances in this area and the future of treatments for bacterial infections.

[Impact of the use of an early neonatal sepsis calculator]. / Impacto del uso de una calculadora de riesgo de sepsis neonatal temprana.

BACKGROUND: Early onset neonatal sepsis (EOS) is a public health problem; antibiotic treatment is often unnecessary and can increase morbimortality. EOS risk calculator are available that allows limiting the use of antibiotics. OBJECTIVE: To compare the patterns of antibiotic use and hospitalization time in infant newborns (NB) ≥ 34 weeks of gestational age (GA) in a historical cohort attended from November 2017 to April 2018 vs. a prospective cohort from November 2018 to April 2019, before and after implementing the use of an EOS risk calculator, respectively. MATERIAL AND METHODS: Ambispective, observational, longitudinal, analytical study in infants NB ≥ 34 GA attended before and after implementing the use of an EOS risk calculator. The patterns of antibiotic´s use were compared. Simple frequencies and proportions, means and standard deviations or medians with ranges, Mann-Whitney U Test and Chi square test with SPSS V. 20.0 statistical package were used; considering significant values of p < 0.05. RESULTS: Thirty patients were included, 15 NB for each period, the gestational age average was 36.8 ± 2.3 GA. there was no statistically significant difference in the frequency of diagnosis of EOS with blood culture or days of hospital stay. Antibiotics were beginning in all the infants attended before the implementation of the EOS risk calculator, unlike 46.7% of the infants after its implementation (p = 0.001). CONCLUSIONS: The EOS risk calculator is an easy tool to use, and demonstrated to be useful in decreasing unnecessary use of antibiotics.

INTRODUCCIÓN: la sepsis neonatal temprana (SNT) es un problema de salud pública. El tratamiento con antibióticos frecuentemente es innecesario y no inocuo. El uso de calculadoras de riesgo de SNT permite disminuir el uso injustificado de antibióticos. OBJETIVO: comparar el uso de antibióticos y tiempo de hospitalización en recién nacidos (RN) ≥ 34 semanas de gestación (SDG) en una cohorte histórica atendida de noviembre de 2017 a abril de 2018 frente a una cohorte prospectiva de noviembre de 2018 a abril del 2019, antes y después de la implementación del uso de una calculadora de riesgo de SNT. MATERIAL Y MÉTODOS: estudio ambispectivo, observacional, analítico en RN ≥ 34 SDG atendidos antes y después de implementar una calculadora de riesgo de SNT. Se comparó el uso de antibióticos así como el tiempo de hospitalización. Se usaron frecuencias, proporciones, medidas de tendencia central y dispersión, U de Mann-Whitney y Chi cuadrada, con el paquete estadístico SPSS V. 20.0; siendo significativos los valores de p < 0.05. RESULTADOS: se incluyeron 30 pacientes, 15 para cada grupo, de 36.8 ± 2.3 SDG. No hubo diferencia significativa en la frecuencia de diagnóstico de SNT con hemocultivo ni en los días de estancia intrahospitalaria. Se usó antibióticos en el 100% de los RN antes frente al 46.7% después del uso de la calculadora (p = 0.001). CONCLUSIONES: la calculadora de riesgo de SNT es una herramienta de uso sencillo y que demostró ser útil para disminuir el uso innecesario de antibióticos.

Successful mobilization with AMD3100 and filgrastim with engraftment of autologous peripheral blood stem cells in a heavily pretreated pediatric patient with recurrent Burkitt lymphoma.

The authors report a case of a 13-year-old female with recurrent Burkitt lymphoma who was heavily pretreated with chemotherapy. During chemotherapy for relapse, she developed serious aspergillus infection of the palate and sinuses. Despite 10 microg/kg of filgrastim for 5 days, peripheral blood CD34(+) cells remained

Phages for Biofilm Removal.

Biofilms are clusters of bacteria that live in association with surfaces. Their main characteristic is that the bacteria inside the biofilms are attached to other bacterial cells and to the surface by an extracellular polymeric matrix. Biofilms are capable of adhering to a wide variety of surfaces, both biotic and abiotic, including human tissues, medical devices, and other materials. On these surfaces, biofilms represent a major threat causing infectious diseases and economic losses. In addition, current antibiotics and common disinfectants have shown limited ability to remove biofilms adequately, and phage-based treatments are proposed as promising alternatives for biofilm eradication. This review analyzes the main advantages and challenges that phages can offer for the elimination of biofilms, as well as the most important factors to be taken into account in order to design effective phage-based treatments.

The evolution of relapse of adult T cell acute lymphoblastic leukemia.

BACKGROUND: Adult T cell acute lymphoblastic leukemia (T-ALL) is a rare disease that affects less than 10 individuals in one million. It has been less studied than its cognate pediatric malignancy, which is more prevalent. A higher percentage of the adult patients relapse, compared to children. It is thus essential to study the mechanisms of relapse of adult T-ALL cases. RESULTS: We profile whole-genome somatic mutations of 19 primary T-ALLs from adult patients and the corresponding relapse malignancies and analyze their evolution upon treatment in comparison with 238 pediatric and young adult ALL cases. We compare the mutational processes and driver mutations active in primary and relapse adult T-ALLs with those of pediatric patients. A precise estimation of clock-like mutations in leukemic cells shows that the emergence of the relapse clone occurs several months before the diagnosis of the primary T-ALL. Specifically, through the doubling time of the leukemic population, we find that in at least 14 out of the 19 patients, the population of relapse leukemia present at the moment of diagnosis comprises more than one but fewer than 108 blasts. Using simulations, we show that in all patients the relapse appears to be driven by genetic mutations. CONCLUSIONS: The early appearance of a population of leukemic cells with genetic mechanisms of resistance across adult T-ALL cases constitutes a challenge for treatment. Improving early detection of the malignancy is thus key to prevent its relapse.

The Sonozotz project: Assembling an echolocation call library for bats in a megadiverse country.

Bat acoustic libraries are important tools that assemble echolocation calls to allow the comparison and discrimination to confirm species identifications. The Sonozotz project represents the first nation-wide library of bat echolocation calls for a megadiverse country. It was assembled following a standardized recording protocol that aimed to cover different recording habitats, recording techniques, and call variation inherent to individuals. The Sonozotz project included 69 species of echolocating bats, a high species richness that represents 50% of bat species found in the country. We include recommendations on how the database can be used and how the sampling methods can be potentially replicated in countries with similar environmental and geographic conditions. To our knowledge, this represents the most exhaustive effort to date to document and compile the diversity of bat echolocation calls for a megadiverse country. This database will be useful to address a range of ecological questions including the effects of anthropogenic activities on bat communities through the analysis of bat sound.

Elements of metacommunity structure of Paraguayan bats: multiple gradients require analysis of multiple ordination axes.

Techniques to evaluate elements of metacommunity structure (EMS; coherence, species turnover and range boundary clumping) have been available for several years. Such approaches are capable of determining which idealized pattern of species distribution best describes distributions in a metacommunity. Nonetheless, this approach rarely is employed and such aspects of metacommunity structure remain poorly understood. We expanded an extant method to better investigate metacommunity structure for systems that respond to multiple environmental gradients. We used data obtained from 26 sites throughout Paraguay as a model system to demonstrate application of this methodology. Using presence-absence data for bats, we evaluated coherence, species turnover and boundary clumping to distinguish among six idealized patterns of species distribution. Analyses were conducted for all bats as well as for each of three feeding ensembles (aerial insectivores, frugivores and molossid insectivores). For each group of bats, analyses were conducted separately for primary and secondary axes of ordination as defined by reciprocal averaging. The Paraguayan bat metacommunity evinced Clementsian distributions for primary and secondary ordination axes. Patterns of species distribution for aerial insectivores were dependent on ordination axis, showing Gleasonian distributions when ordinated according to the primary axis and Clementsian distributions when ordinated according to the secondary axis. Distribution patterns for frugivores and molossid insectivores were best described as random. Analysis of metacommunities using multiple ordination axes can provide a more complete picture of environmental variables that mold patterns of species distribution. Moreover, analysis of EMS along defined gradients (e.g., latitude, elevation and depth) or based on alternative ordination techniques may complement insights based on reciprocal averaging because the fundamental questions addressed in analyses are contingent on the ordination technique that is employed.

[Recommendations for vaccination against ROTAvirus in PREMature newborns (ROTAPREM)]. / Recomendaciones para la vacunación frente al ROTAvirus de los recién nacidos PREMaturos (ROTAPREM).

Rotavirus (RV) is the leading cause of severe acute gastroenteritis in infants worldwide. Most children are infected by RV by the age of 5years, and especially in the first 2years. Two oral attenuated vaccines against RV are licensed in industrialised countries, which have proven to be safe and effective against the disease. The main objective of these vaccines has been to reproduce the natural history of infection and protect against severe disease in the first months of life. Preterm infants are at higher risk of severe RV infection compared to full-term infants and infants with normal birth weight. Data collected on RV vaccination in preterm infants demonstrated that RV vaccines are effective and safe, compared with full-term infants, with a marginal risk of horizontal viral transmission and dissemination when vaccination is performed during hospitalisation. Preterm infants frequently require admission to hospital after the beginning of the 12th week of life, which suggests that they should receive RV vaccines during admission according to the official immunisation schedule.