Diagnostic Approach to Interstitial Lung Diseases Associated with Connective Tissue Diseases.

Interstitial lung disorders are a group of respiratory diseases characterized by interstitial compartment infiltration, varying degrees of infiltration, and fibrosis, with or without small airway involvement. Although some are idiopathic (e.g., idiopathic pulmonary fibrosis, idiopathic interstitial pneumonias, and sarcoidosis), the great majority have an underlying etiology, such as systemic autoimmune rheumatic disease (SARD, also called Connective Tissue Diseases or CTD), inhalational exposure to organic matter, medications, and rarely, genetic disorders. This review focuses on diagnostic approaches in interstitial lung diseases associated with SARDs. To make an accurate diagnosis, a multidisciplinary, personalized approach is required, with input from various specialties, including pulmonary, rheumatology, radiology, and pathology, to reach a consensus. In a minority of patients, a definitive diagnosis cannot be established. Their clinical presentations and prognosis can be variable even within subsets of SARDs.

Pediatric pyoderma gangrenosum with pulmonary involvement: A case report.

Pyoderma gangrenosum is a rare disease in childhood. Extra-cutaneous manifestations are uncommon in pyoderma gangrenosum, even more so in children, with only a few cases reported in the literature. We present the case of a pediatric patient with pyoderma gangrenosum and associated pulmonary involvement. In this case, the diagnosis was delayed leading to late initiation of therapy, emphasizing the importance of maintaining a high level of suspicion for this diagnosis.

Global DNA methylation and telomere length as markers of accelerated aging in people living with HIV and non-alcoholic fatty liver disease.

Metabolic-dysfunction-associated fatty liver disease (MAFLD) is a comorbidity that generally increases in people living with HIV (PLWH). This condition is usually accompanied by persistent inflammation and premature immune system aging. In this prospective cohort study, we describe a straightforward methodology for quantifying biomarkers of aging, such as DNA methylation and telomere length, in PLWH and in the context of another relevant condition, such as MAFLD. Fifty-seven samples in total, thirty-eight from PLWH and nineteen from non-PLWH participants with or without MAFLD, were obtained and subjected to DNA extraction from peripheral blood mononuclear cells (PBMCs). Global DNA methylation and telomere length quantification were performed using an adapted enzyme-linked immunosorbent assay (ELISA) and qPCR, respectively. The quantification results were analysed and corrected by clinically relevant variables in this context, such as age, sex, and metabolic syndrome. Our results show an increased association of these biomarkers in PLWH regardless of their MAFLD status. Thus, we propose including the quantification of these age-related factors in studies of comorbidities. This will allow a better understanding of the effect of comorbidities of HIV infection and MAFLD and prevent their effects in these populations in the future.

Tropical butterflies use thermal buffering and thermal tolerance as alternative strategies to cope with temperature increase.

Climate change poses a severe threat to many taxa, with increased mean temperatures and frequency of extreme weather events predicted. Insects can respond to high temperatures using behaviour, such as angling their wings away from the sun or seeking cool local microclimates to thermoregulate or through physiological tolerance. In a butterfly community in Panama, we compared the ability of adult butterflies from 54 species to control their body temperature across a range of air temperatures (thermal buffering ability), as well as assessing the critical thermal maxima for a subset of 24 species. Thermal buffering ability and tolerance were influenced by family, wing length, and wing colour, with Pieridae, and butterflies that are large or darker in colour having the strongest thermal buffering ability, but Hesperiidae, small, and darker butterflies tolerating the highest temperatures. We identified an interaction between thermal buffering ability and physiological tolerance, where species with stronger thermal buffering abilities had lower thermal tolerance, and vice versa. This interaction implies that species with more stable body temperatures in the field may be more vulnerable to increases in ambient temperatures, for example heat waves associated with ongoing climate change. Our study demonstrates that tropical species employ diverse thermoregulatory strategies, which is also reflected in their sensitivity to temperature extremes.

El cambio climático representa una grave amenaza para muchos taxones, con un aumento de las temperaturas medias y la frecuencia de eventos climáticos extremos pronosticados. Los insectos pueden responder a las altas temperaturas mediante comportamientos, como inclinar sus alas fuera del alcance del sol o buscar microclimas frescos locales para termorregular, o a través de la tolerancia fisiológica. En una comunidad de mariposas en Panamá, comparamos la capacidad de las mariposas adultas de 54 especies para controlar su temperatura corporal en un rango de temperaturas del aire (capacidad de amortiguación térmica), así como evaluar el máximo térmico crítico para un subconjunto de 24 especies. La capacidad de amortiguación térmica y la tolerancia se influenciaron por la familia, la longitud del ala y el colour del ala; con Pieridae y mariposas grandes o de colour más oscuro teniendo la capacidad de amortiguación térmica más fuerte, pero Hesperiidae, mariposas pequeñas y de colour más oscuro tolerando las temperaturas más altas. Identificamos una relación entre la capacidad de amortiguación térmica y la tolerancia fisiológica, en la que las especies con mayores capacidades de amortiguación térmica tenían una menor tolerancia térmica, y viceversa. Esta interacción implica que las especies con temperaturas corporales más estables en el campo pueden ser más vulnerables a los aumentos en las temperaturas ambientales, por ejemplo, las olas de calor asociadas con el cambio climático actual. Nuestra investigación demuestra que las especies tropicales emplean diversas estrategias de termorregulación, las cuales también se reflejan en su sensibilidad a las temperaturas extremas.

Organotypic Hippocampal Slice Cultures from Adult Tauopathy Mice and Theragnostic Evaluation of Nanomaterial Phospho-TAU Antibody-Conjugates.

Organotypic slice culture models surpass conventional in vitro methods in many aspects. They retain all tissue-resident cell types and tissue hierarchy. For studying multifactorial neurodegenerative diseases such as tauopathies, it is crucial to maintain cellular crosstalk in an accessible model system. Organotypic slice cultures from postnatal tissue are an established research tool, but adult tissue-originating systems are missing, yet necessary, as young tissue-originating systems cannot fully model adult or senescent brains. To establish an adult-originating slice culture system for tauopathy studies, we made hippocampal slice cultures from transgenic 5-month-old hTau.P301S mice. In addition to the comprehensive characterization, we set out to test a novel antibody for hyperphosphorylated TAU (pTAU, B6), with and without a nanomaterial conjugate. Adult hippocampal slices retained intact hippocampal layers, astrocytes, and functional microglia during culturing. The P301S-slice neurons expressed pTAU throughout the granular cell layer and secreted pTAU to the culture medium, whereas the wildtype slices did not. Additionally, cytotoxicity and inflammation-related determinants were increased in the P301S slices. Using fluorescence microscopy, we showed target engagement of the B6 antibody to pTAU-expressing neurons and a subtle but consistent decrease in intracellular pTAU with the B6 treatment. Collectively, this tauopathy slice culture model enables measuring the extracellular and intracellular effects of different mechanistic or therapeutic manipulations on TAU pathology in adult tissue without the hindrance of the blood-brain barrier.

A Polygenic Risk Score for Idiopathic Pulmonary Fibrosis and Interstitial Lung Abnormalities.

Rationale: In addition to rare genetic variants and the MUC5B locus, common genetic variants contribute to idiopathic pulmonary fibrosis (IPF) risk. The predictive power of common variants outside the MUC5B locus for IPF and interstitial lung abnormalities (ILAs) is unknown. Objectives: We tested the predictive value of IPF polygenic risk scores (PRSs) with and without the MUC5B region on IPF, ILA, and ILA progression. Methods: We developed PRSs that included (PRS-M5B) and excluded (PRS-NO-M5B) the MUC5B region (500-kb window around rs35705950-T) using an IPF genome-wide association study. We assessed PRS associations with area under the receiver operating characteristic curve (AUC) metrics for IPF, ILA, and ILA progression. Measurements and Main Results: We included 14,650 participants (1,970 IPF; 1,068 ILA) from six multi-ancestry population-based and case-control cohorts. In cases excluded from genome-wide association study, the PRS-M5B (odds ratio [OR] per SD of the score, 3.1; P = 7.1 × 10-95) and PRS-NO-M5B (OR per SD, 2.8; P = 2.5 × 10-87) were associated with IPF. Participants in the top PRS-NO-M5B quintile had ∼sevenfold odds for IPF compared with those in the first quintile. A clinical model predicted IPF (AUC, 0.61); rs35705950-T and PRS-NO-M5B demonstrated higher AUCs (0.73 and 0.7, respectively), and adding both genetic predictors to a clinical model yielded the highest performance (AUC, 0.81). The PRS-NO-M5B was associated with ILA (OR, 1.25) and ILA progression (OR, 1.16) in European ancestry participants. Conclusions: A common genetic variant risk score complements the MUC5B variant to identify individuals at high risk of interstitial lung abnormalities and pulmonary fibrosis.

Thermoregulatory ability and mechanism do not differ consistently between neotropical and temperate butterflies.

Climate change is a major threat to species worldwide, yet it remains uncertain whether tropical or temperate species are more vulnerable to changing temperatures. To further our understanding of this, we used a standardised field protocol to (1) study the buffering ability (ability to regulate body temperature relative to surrounding air temperature) of neotropical (Panama) and temperate (the United Kingdom, Czech Republic and Austria) butterflies at the assemblage and family level, (2) determine if any differences in buffering ability were driven by morphological characteristics and (3) used ecologically relevant temperature measurements to investigate how butterflies use microclimates and behaviour to thermoregulate. We hypothesised that temperate butterflies would be better at buffering than neotropical butterflies as temperate species naturally experience a wider range of temperatures than their tropical counterparts. Contrary to our hypothesis, at the assemblage level, neotropical species (especially Nymphalidae) were better at buffering than temperate species, driven primarily by neotropical individuals cooling themselves more at higher air temperatures. Morphology was the main driver of differences in buffering ability between neotropical and temperate species as opposed to the thermal environment butterflies experienced. Temperate butterflies used postural thermoregulation to raise their body temperature more than neotropical butterflies, probably as an adaptation to temperate climates, but the selection of microclimates did not differ between regions. Our findings demonstrate that butterfly species have unique thermoregulatory strategies driven by behaviour and morphology, and that neotropical species are not likely to be more inherently vulnerable to warming than temperate species.

El calentamiento global es una gran amenaza para las especies alrededor del mundo, sin embargo, no se tiene bien definido sí en los insectos, las especies distribuídas en las zonas tropicales son más vulnerables a los cambios de temperature que las especies de zonas templadas o viceversa. Para responder a este interrogante, utilizamos un protocolo de campo estandarizado aplicado a especies de mariposas distribuídas en zonas tropicales (Panamá) versus zonas templadas (Reino Unido, República Checa y Austria), con el cual buscamos: (1) Evaluar la capacidad de amortiguación (capacidad de regular la temperatura corporal en relación con la temperatura del aire circundante) en el a nivel de ensamblaje y familia, (2) Determinar sí las diferencias en la capacidad de amortiguación es facilitada por sus características morfológicas, y (3) Investigar cómo las mariposas usan los microclimas y el comportamiento para termorregularse a tráves de mediciones de temperatura ecológicamente relevantes. Nuestra hipotesis incial soportaba que las mariposas templadas estaban adaptadas para amortiguar los cambios de temperatura en comparación con las mariposas neotropicales, ya que las especies templadas experimentan un rango más amplio de temperaturas que sus contrapartes tropicales. Contrariamente a nuestra hipótesis, a nivel de ensamble, las especies neotropicales (especialmente familia Nymphalidae) fueron mejores en la capaicidad de amortiguacion que las especies templadas, explicado por el hecho de que individuos se enfrían más a altas temperaturas del aire. Así, la morfología fué el principal impulsor de las diferencias en la capacidad de amortiguación entre las especies neotropicales y templadas en comparación con el ambiente térmico experimentado por las mismas. Encontramos que las mariposas templadas utilizaron la termorregulación de postura para elevar su temperatura corporal más que las mariposas neotropicales, probablemente como una adaptación a los climas templados, aunque la selección de microclimas no difirió entre regiones. Nuestros hallazgos demuestran que las especies de mariposas tienen estrategias de termorregulación únicas, impulsadas principalmente por el comportamiento y morfología, además nuestros resultados demuestran que a diferencia de lo que se ha pensado, las especies neotropicales son igual de vulnerables al calentamiento de su hábitat que las especies templadas.

A Case Series of Spontaneous Pneumomediastinum With/Without Pneumothorax in COVID-19.

With the previous worldwide initial coronavirus disease 2019 (COVID-19) pandemic, a notable rise in spontaneous pneumomediastinum with/without pneumothorax (SPP) has been noted. Most cases were initially reported as complications secondary to barotrauma from mechanical ventilation (MV) with COVID-19. However, with the Delta strain, starting from December 2020, there have been multiple reports of SPP. The SPP is an uncommon complication outside use of assisted ventilation with either noninvasive positive pressure ventilation (NIPPV) or MV. COVID-19 has been linked to higher incidence of SPP without use of NIPPV or MV. We present a series of 5 cases with a polymerase chain reaction-confirmed COVID-19 diagnostic testing whose hospital course was complicated by SPP unrelated to the use of either NIPPV or MV.

Evolution of SARS-CoV-2 during the first year of the COVID-19 pandemic in Northwestern Argentina.

Studies about the evolution of SARS-CoV-2 lineages in different backgrounds such as naive populations are still scarce, especially from South America. This work aimed to study the introduction and diversification pattern of SARS-CoV-2 during the first year of the COVID-19 pandemic in the Northwestern Argentina (NWA) region and to analyze the evolutionary dynamics of the main lineages found. In this study, we analyzed a total of 260 SARS-CoV-2 whole-genome sequences from Argentina, belonging to the Provinces of Jujuy, Salta, and Tucumán, from March 31st, 2020, to May 22nd, 2021, which covered the full first wave and the early second wave of the COVID-19 pandemic in Argentina. In the first wave, eight lineages were identified: B.1.499 (76.9%), followed by N.5 (10.2%), B.1.1.274 (3.7%), B.1.1.348 (3.7%), B.1 (2.8%), B.1.600 (0.9%), B.1.1.33 (0.9%) and N.3 (0.9%). During the early second wave, the first-wave lineages were displaced by the introduction of variants of concern (VOC) (Alpha, Gamma), or variants of interest (VOI) (Lambda, Zeta, Epsilon) and other lineages with more limited distribution. Phylodynamic analyses of the B.1.499 and N.5, the two most prevalent lineages in the NWA, revealed that the rate of evolution of lineage N.5 (7.9 × 10-4 substitutions per site per year, s/s/y) was a ∼40% faster than that of lineage B.1.499 (5.6 × 10-4 s/s/y), although both are in the same order of magnitude than other non-VOC lineages. No mutations associated with a biological characteristic of importance were observed as signatures markers of the phylogenetic groups established in Northwestern Argentina, however, single sequences in non-VOC lineages did present mutations of biological importance or associated with VOCs as sporadic events, showing that many of these mutations could emerge from circulation in the general population. This study contributed to the knowledge about the evolution of SARS-CoV-2 in a pre-vaccination and without post-exposure immunization period.

Human Monkeypox in People With HIV: Transmission, Clinical Features, and Outcome.

We describe the first 25 persons with HIV diagnosed with human monkeypox virus (MPXV) in our hospital in an ongoing outbreak in Spain. Proctitis was the predominant finding in 52%, and MPXV DNA was detected in rectal swabs from 90%. Proctitis and demonstration of MPXV in rectal swabs support the sexual transmission of MPXV.

Use of Tenofovir Alafenamide/Emtricitabine/Elvitegravir-Cobicistat in HIV-Naive Patients with Advanced Disease: GENIS Study.

Objective: The primary endpoint of the study was to determine the proportion of patients with HIV RNA < 50 copies/mL at 48 weeks. Design: Phase IV, multicentric, open-label, single-arm clinical trial of participants recruited in 2018−2019 to evaluate the efficacy and safety of tenofovir alafenamide/emtricitabine/elvitegravir-cobicistat (TAF/FTC/EVG-c) as first-line treatment in HIV-1 infected naïve participants with advanced disease. Methods: Adverse events were graded according to the Division of AIDS scale version 2.0. Quantitative variables were recorded as median and interquartile range, and qualitative variables as absolute number and percentage. T-Student or Wilcoxon tests were used to analyze intragroup differences of the continuous variables. Results: Fifty participants were recruited with a baseline median CD4 lymphocyte count of 116 cells/µL and a viral load of 218,938 copies/mL. The proportion of patients with viral load <50 copies/mL at week 48 was 94% in the per-protocol analysis, with a median time of 1.9 months to achieve it. Three adverse events attributed to the study drug caused trial discontinuation. Conclusions: the use of TAF/FTC/EVG-c in patients with advanced HIV disease in our study demonstrated efficacy comparable to data from pivotal clinical trials with a good safety profile.

Diaphragm Ultrasonography to Predict Noninvasive Respiratory Treatment Failure in Infants With Severe Bronchiolitis.

BACKGROUND: Noninvasive respiratory support is commonly used in treatment of bronchiolitis. Determinants of failure are needed to prevent delayed intubation. METHODS: We conducted a prospective observational pilot study in infants admitted to a pediatric ICU. Diaphragmatic excursion (dExc), diaphragmatic inspiratory/expiratory time, and diaphragmatic thickening fraction (dTF) were recorded at admission, 24 h, and 48 h in both hemidiaphragms. RESULTS: Twenty-six subjects were included (14 on HFNC and 12 on NIV) with a total of 56 ultrasonographic evaluations. Three subjects required invasive ventilation. Sixty-four percent of the subjects on HFNC required NIV as rescue therapy and 2/14 invasive ventilation (14.2%). In the HFNC group there were no differences in dExc between those who required escalation to NIV or invasive ventilation and those who didn't. Left dTF was higher in subjects on HFNC requiring invasive ventilation versus those needing NIV (left dTF 47% vs 22% [13-30]; P = .046, r = 0.7). Diaphragmatic I:E ratios were higher in infants on HFNC requiring invasive ventilation and diaphragmatic expiratory time was shorter (left P = .038; right P = .02). In the NIV group there were no differences in dExc, I:E ratios, or dTF between subjects needing escalation to invasive ventilation and those who didn't. We found no correlation between a clinical work of breathing score and echographic dTF. CONCLUSIONS: In infants with moderate or severe bronchiolitis receiving HFNC, the use of ultrasonographic left dTF could help predict respiratory treatment failure and need for invasive ventilation. The use of ultrasonographic dExc is of little help to predict both.

Molecular diagnosis of bacteremia in a pediatric intensive care unit: a step forward.

Aim: T2Bacteria® Panel detects six ESKAPE pathogens in around 3.5 h directly in whole blood. Our aim was to compare T2Bacteria with simultaneous blood culture in critically ill children with suspected bloodstream infection. Materials & methods: Retrospective study of critically ill children admitted to our tertiary-care center (2018-2020). Results: A total of 60 patients were recruited, including 63 episodes and 75 T2Bacteria/blood cultures were performed. Overall agreement between T2Bacteria and blood culture was 78.7% with a discordance of 21.3% (16/75 samples). Conclusion: T2Bacteria Panel may be useful in critically ill children providing an accurate and fast diagnosis of bacteremia directly from blood sample and detecting pathogens not recovered in blood cultures.

Acute Hypoxemic Respiratory Failure in Children at the Start of COVID-19 Outbreak: A Nationwide Experience.

STUDY DESIGN: This is a prospective, multicenter, and observational study with the aim of describing physiological characteristics, respiratory management, and outcomes of children with acute hypoxemic respiratory failure (AHRF) from different etiologies receiving invasive mechanical ventilation (IMV) compared with those affected by SARS-CoV-2. METHODS AND MAIN RESULTS: Twenty-eight patients met the inclusion criteria: 9 patients with coronavirus disease 2019 (COVID-19) and 19 patients without COVID-19. Non-COVID-19 patients had more pre-existing comorbidities (78.9% vs. 44.4%) than COVID-19 patients. At AHRF onset, non-COVID-19 patients had worse oxygenation (PaO2/FiO2 = 95 mmHg (65.5-133) vs. 150 mmHg (105-220), p = 0.04), oxygenation index = 15.9 (11-28.4) vs. 9.3 (6.7-10.6), p = 0.01), and higher PaCO2 (48 mmHg (46.5-63) vs. 41 mmHg (40-45), p = 0.07, that remained higher at 48 h: 54 mmHg (43-58.7) vs. 41 (38.5-45.5), p = 0.03). In 12 patients (5 COVID-19 and 7 non-COVID-19), AHRF evolved to pediatric acute respiratory distress syndrome (PARDS). All non-COVID-19 patients had severe PARDS, while 3 out of 5 patients in the COVID-19 group had mild or moderate PARDS. Overall Pediatric Intensive Care Medicine (PICU) mortality was 14.3%. CONCLUSIONS: Children with AHRF due to SARS-CoV2 infection had fewer comorbidities and better oxygenation than patients with non-COVID-19 AHRF. In this study, progression to severe PARDS was rarely observed in children with COVID-19.

Organoplatinum(II) Complexes Self-Assemble and Recognize AT-Rich Duplex DNA Sequences.

The specific recognition of AT-rich DNA sequences opens up the door to promising diagnostic and/or therapeutic strategies against gene-related diseases. Here, we demonstrate that amphiphilic PtII complexes of the type [Pt(dmba)(N∧N)]NO3 (dmba = N,N-dimethylbenzylamine-κN, κC; N∧N = dpq (3), dppz (4), and dppn (5)) recognize AT-rich oligonucleotides over other types of DNA, RNA, and model proteins. The crystal structure of 4 shows the presence of significant π-stacking interactions and a distorted coordination sphere of the d8 PtII atom. Complex 5, containing the largest π-conjugated ligand, forms supramolecular assemblies at high concentrations under aqueous environment. However, its aggregation can be promoted in the presence of DNA at concentrations as low as 10 µM in a process that "turns on" its excimer emission around 600 nm. Viscometry, gel electrophoresis, and theoretical calculations demonstrate that 5 binds to minor groove when self-assembled, while the monomers of 3 and 4 intercalate into the DNA. The complexes also inhibit cancer cell growth with low-micromolar IC50 values in 2D tissue culture and suppress tumor growth in 3D tumor spheroids with a multicellular resistance (MCR) index comparable to that of cisplatin.

Severe Acute Respiratory Syndrome Coronavirus 2 Spreads to Lymph Nodes and Strongly Expands CD4+ Effector Memory RA Cells in a Patient With Mild Coronavirus Disease 2019.

A woman with mild coronavirus disease 2019 developed cervical adenopathy, being diagnosed of Epstein-Barr virus infectious mononucleosis. We performed fine needle aspiration, and demonstrate that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is found in lymph nodes even in mild disease along with a strong expansion of terminally differentiated effector memory CD4+ T cells, a cell population that is practically absent in lymph nodes.

Label-Free Iron Oxide Nanoparticles as Multimodal Contrast Agents in Cells Using Multi-Photon and Magnetic Resonance Imaging.

INTRODUCTION: The inherent fluorescence properties of iron oxide nanoparticles (IONPs) were characterized, and their applicability for multiphoton imaging in cells was tested in combination with their magnetic resonance imaging (MRI) capabilities. METHODS: Superparamagnetic iron oxide nanoparticles were synthesized and subsequently coated with polyethylene glycol to make them water-dispersible. Further characterization of the particles was performed using Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), dynamic light scattering (DLS), superconducting quantum interference device (SQUID) and magnetic resonance relaxivity measurements. MRI and fluorescence properties of bare IONPs were first studied in solution and subsequently in A549-labeled cells. RESULTS: The particles, with a core size of 11.3 ± 4.5 nm, showed a good negative MRI contrast in tissue-mimicking phantoms. In vitro studies in mammalian A549 cells demonstrate that these IONPs are biocompatible and can also produce significant T2/T2* contrast enhancement in IONPs-labeled cells. Furthermore, excitation-wavelength dependent photoluminescence was observed under one- and two-photon excitation. DISCUSSION: The obtained results indicated that IONPs could be used for fluorescence label-free bioimaging at multiple wavelengths, which was proven by multiphoton imaging of IONPs internalization in A549 cancer cells.