Revisión de la sedación continua en el paciente crítico. Evidencias de la efectividad de nuevos fármacos respecto a los esquemas farmacológicos tradicionales / Review of continuous sedation in the critical ill patient. Evidence of the effectiveness of new drugs compared to traditional pharmacological schemes

Introducción: La sedación es uno de los pilares fundamentales del manejo del paciente crítico internado en la Unidad de Terapia Intensiva (UTI), sobre todo en aquellos que requieren Asistencia Ventilatoria Mecánica (AVM). Los fármacos que se utilizan con este propósito tienen el objetivo de lograr un adecuado nivel de conciencia en el paciente, de forma tal que se encuentre confortable y tolere la AVM. Los esquemas de sedación utilizados se encontraban basados en Benzodiacepinas, aunque, su uso no está exento de efectos adversos. El presente estudio pretende realizar una Revisión y Síntesis de la evidencia existente sobre la efectividad y seguridad del uso de dos nuevos fármacos, Propofol y Dexmedetomidina, para sedación continua en UTI y su comparación con los esque- mas tradicionales. Los Resultados respecto a la reducción de días en UTI resultó siempre significativa a favor del uso de propofol o dexmedetomidina en comparación a benzodiacepinas; lo mismo ocurrió con los días vinculados a la AVM. Estos resultados fueron encontrados en revisiones tanto de alta calidad como moderada o baja. Sin embargo, todos los estudios tuvieron en común que la calidad de la evidencia utilizada fue baja a moderada. Según la evidencia identificada, el uso de dexmedetomidina o propofol disminuiría de manera estadísticamente significativa los días de estadía en UTI y los requerimientos de AVM en pacientes adultos. Se debe tener en cuenta que la mayoría de las Revisiones encontradas fueron de calidad baja, siendo solamente 2 (dos) de calidad alta y una moderada. Es por esto último que la recomendación del uso de sedación basada en Dexmedetomidina o Propofol es condicional, ya que la calidad de la evidencia que la soporta es baja, en la mayoría de los casos.

Introductión: Sedation is one of the fundamental pillars of the management of critically ill patients admitted to the Intensive Care Unit (ICU), especially in those who require mechanical ventilatory assistance (MVA). The drugs used for this purpose have the objective of achieving an adequate level of consciousness in the patient, so that they are comfortable and tolerate AVM. The sedation schemes used were based on Benzodiazepines, however, their use is not free of adverse effects. The present work aims to carry out a review and synthesis of the existing evidence on the effectiveness and safety of the use of two new drugs Propofol and Dexmedetomidine for continuous sedation in ICU and its comparison with traditional regimens. The results regarding the reduction of days in ICU were always significant in favor of the use of Propofol or Dexmedetomidine compared to benzodiazepines; The same happened with the days linked to the AVM. These results were found in reviews of both high and moderate or low quality. However, what they all had in common was that the quality of the evidence used was low to moderate. According to the evidence identified, the use of Dexmedetomidine or Propofol would statistically significantly reduce the days of ICU stay and AVM requirements in adult patients. It should be taken into account that most of the reviews found were of low quality, with only 2 being of high quality, and 1 of moderate quality. It is for this last reason that the recommendation for the use of sedation based on Dexmedetomidine or Propofol is conditional, since the quality of the evidence supporting it is, for the most part, low.

Encefalitis de Hashimoto. Presentación de un caso / Hashimoto Encephalitis. Case Report

INTRODUCCIÓN La Encefalitis de Hashimoto (EH) es una encefalopatía de naturaleza autoinmune, con buena respuesta al tratamiento con corticoides, títulos séricos elevados de anticuerpos antitiroideos y de curso subagudo con recaídas-remisiones. Es una enfermedad poco frecuente, con una presentación clínica variable y fisiopatología aún desconocida. PRESENTACIÓN DEL CASO: Paciente femenina de 76 años con antecedentes de hipotiroidismo primario. Ingresó con un síndrome confusional agudo. Al examen físico vigil, Glasgow 13/15, subfebril (37.8°C) desorientada temporoespacialmente, ecolalia, pupilas isocóricas y reactivas, sin focalidad neurológica. Signos meníngeos negativos. Laboratorio: Hipocalcemia leve (7.8mg/dl), hipopotasemia (K 3,2 mmol/l), PCR 221.9 mg/L. Test rápido para VIH negativo. TC de encéfalo sin alteraciones. Punción lumbar líquido cristal de roca, proteínas 1 g/l, glucosa 0.67 g/l, láctico 1.3, leucocitos 77 células/microL (100% mononucleares). Se interpretó inicialmente como Encefalitis de etiología viral y se le indicó aciclovir. Presentó sensorio alternante, excitación psicomotriz y convulsión tónica clónica generalizada. Debido a deterioro súbito del sensorio, se realizó intubación orotraqueal y se trasladó a Unidad de Terapia Intensiva (UTI). Permaneció bajo asistencia mecánica ventilatoria y con vasopresores. Laboratorio: VDRL, p24 y anticuerpos HIV negativos, TSH 27,82, T4 0,41. PCR de LCR: Virus herpes simple 1 y 2, citomegalovirus y JC negativos. Hemocultivos negativos. Ante sospecha clínica de Encefalitis de Hashimoto, se solicitaron anticuerpos antitiroideo peroxidasa (aTPO), antitiroglobulina (aTG) y Anticuerpos Anti-Receptor de TSH (TRABS), que resultaron positivos. Recibió tratamiento con levotiroxina endovenosa e hidrocortisona. Normaliza valores. Por fallo en el weaning, se realizó traqueostomía. Luego de 21 días de internación en Terapia Intensiva pasó a clínica con posterior alta hospitalaria. Discusión: La EH se puede considerar como diagnóstico, solo después de descartar otras causas. En el caso expuesto se llegó al diagnóstico luego de descartar otras causas posibles, con anticuerpos antitiroideos positivos en altas concentraciones y respuesta al tratamiento con corticoides. Conclusión: Se destaca la necesidad de ampliar el conocimiento de esta patología con el fin de disminuir el subdiagnóstico y promover un inicio precoz del tratamiento, mejorando así su progresión y calidad de vida de los pacientes.

INTRODUCTION: Hashimoto's Encephalitis (HE) is an autoimmune encephalopathy, with a good response to treatment with corticosteroids, high serum titers of antithyroid antibodies and a subacute course with relapses-remissions. It is a rare disease, with a variable clinical presentation and still unknown pathophysiology. CASE REPORT: A 76-year-old female patient with a history of primary hypothyroidism. She was admitted with acute confusional syndrome. On physical examination, she was awake, she was Glasgow 13/15, she was subfebrile (37.8°C), disoriented temporally, echolalia, isochoric and reactive pupils, without neurological focality. Negative meningeal signs. Laboratory: Mild hypocalcemia (7.8 mg/dl), hypokalemia (K 3.2 mmol/l), CRP 221.9 mg/L. Rapid test for HIV negative. Brain CT without alterations. Lumbar puncture rock crystal liquid, proteins 1 g/l, glucose 0.67 g/l, lactic acid 1.3, leukocytes 77 cells/microL (100% mononuclear). It was initially interpreted as Encephalitis of viral etiology and acyclovir was prescribed. He presented alternating sensory, psychomotor excitement, and generalized tonic-clonic seizure. Due to sudden deterioration of the sensorium, orotracheal intubation was performed and he was transferred to the Intensive Care Unit. He remained under mechanical ventilatory assistance and with vasopressors. Laboratory: VDRL, p24 and HIV antibodies negative, TSH 27.82, T4 0.41. CSF PCR: Herpes simplex virus 1 and 2, cytomegalovirus and JC negative. Negative blood cultures. Due to clinical suspicion of Hashimoto's Encephalitis, anti-thyroid peroxidase (aTPO), anti-thyroglobulin (aTG) antibodies and Anti-TSH Receptor Antibodies (TRABS) were requested, which were positive. She was treated with intravenous levothyroxine and hydrocortisone. Normalized values. Due to weaning failure, a tracheostomy was performed. After 21 days of hospitalization in the Intensive Care Unit, she was admitted to the clinic and subsequently discharged from the hospital. Discussion: HD can be considered as a diagnosis, only after ruling out other causes. In the case presented, the diagnosis was made after ruling out other possible causes, with positive antithyroid antibodies in high concentrations and response to treatment with corticosteroids. Conclusion: The need to expand knowledge of this pathology is highlighted in order to reduce underdiagnosis and promote early initiation of treatment, thus improving its progression and quality of life of patients.

Loss of cancer cell-derived ADAM15 alters the tumor microenvironment in colorectal tumors.

Tumor progression and response to treatment are highly affected by interactions between cancer cells and the tumor microenvironment (TME). Many of the soluble factors and signaling receptors involved in this crosstalk are shed by a disintegrin and metalloproteinases (ADAMs). Upregulation of ADAM15 has been linked to worse survival in cancer patients and a tumor-promoting function both in vitro and in murine cancer models. Although ADAM15 has been involved in cell-cell and cell-extracellular matrix interactions, its role in the crosstalk between cancer cells and the TME in vivo remains unexplored. Therefore, we aimed to understand how ADAM15 regulates the cell composition of the TME and how it affects tumor progression. Here, we showed an upregulation of ADAM15 in tumor tissues from rectal cancer patients. Subcutaneous injection of wildtype and ADAM15-knockout CT26 colon cancer cells in syngeneic mice confirmed the protumorigenic role of ADAM15. Profiling of tumors revealed higher immune cell infiltration and cancer cell apoptosis in the ADAM15-deficient tumors. Specifically, loss of ADAM15 led to a reduced number of granulocytes and higher infiltration of antigen-presenting cells, including dendritic cells and macrophages, as well as more T cells. Using in vitro assays, we confirmed the regulatory effect of ADAM15 on macrophage migration and identified ADAM15-derived CYR61 as a potential molecular mediator of this effect. Based on these findings, we speculate that targeting ADAM15 could increase the infiltration of immune cells in colorectal tumors, which is a prerequisite for effective immunotherapy.

Comprehensive phenotypic analysis of diverse FOXN1 variants.

BACKGROUND: Thymus hypoplasia due to stromal cell problems has been linked to mutations in several transcription factors, including Forkhead box N1 (FOXN1). FOXN1 supports T-cell development by regulating the formation and expansion of thymic epithelial cells (TECs). While autosomal recessive FOXN1 mutations result in a nude and severe combined immunodeficiency phenotype, the impact of single-allelic or compound heterozygous FOXN1 mutations is less well-defined. OBJECTIVE: With more than 400 FOXN1 mutations reported, their impact on protein function and thymopoiesis remains unclear for most variants. We developed a systematic approach to delineate the functional impact of diverse FOXN1 variants. METHODS: Selected FOXN1 variants were tested with transcriptional reporter assays and imaging studies. Thymopoiesis was assessed in mouse lines genocopying several human FOXN1 variants. Reaggregate thymus organ cultures were used to compare the thymopoietic potential of the FOXN1 variants. RESULTS: FOXN1 variants were categorized into benign, loss- or gain-of-function, and/or dominant-negatives. Dominant negative activities mapped to frameshift variants impacting the transactivation domain. A nuclear localization signal was mapped within the DNA binding domain. Thymopoiesis analyses with mouse models and reaggregate thymus organ cultures revealed distinct consequences of particular Foxn1 variants on T-cell development. CONCLUSIONS: The potential effect of a FOXN1 variant on T-cell output from the thymus may relate to its effects on transcriptional activity, nuclear localization, and/or dominant negative functions. A combination of functional assays and thymopoiesis comparisons enabled a categorization of diverse FOXN1 variants and their potential impact on T-cell output from the thymus.

AMPKγ3 Controls Muscle Glucose Uptake in Recovery From Exercise to Recapture Energy Stores.

Exercise increases muscle glucose uptake independently of insulin signaling and represents a cornerstone for the prevention of metabolic disorders. Pharmacological activation of the exercise-responsive AMPK in skeletal muscle has been proven successful as a therapeutic approach to treat metabolic disorders by improving glucose homeostasis through the regulation of muscle glucose uptake. However, conflicting observations cloud the proposed role of AMPK as a necessary regulator of muscle glucose uptake during exercise. We show that glucose uptake increases in human skeletal muscle in the absence of AMPK activation during exercise and that exercise-stimulated AMPKγ3 activity strongly correlates to muscle glucose uptake in the postexercise period. In AMPKγ3-deficient mice, muscle glucose uptake is normally regulated during exercise and contractions but impaired in the recovery period from these stimuli. Impaired glucose uptake in recovery from exercise and contractions is associated with a lower glucose extraction, which can be explained by a diminished permeability to glucose and abundance of GLUT4 at the muscle plasma membrane. As a result, AMPKγ3 deficiency impairs muscle glycogen resynthesis following exercise. These results identify a physiological function of the AMPKγ3 complex in human and rodent skeletal muscle that regulates glucose uptake in recovery from exercise to recapture muscle energy stores. ARTICLE HIGHLIGHTS: Exercise-induced activation of AMPK in skeletal muscle has been proposed to regulate muscle glucose uptake in recovery from exercise. This study investigated whether the muscle-specific AMPKγ3-associated heterotrimeric complex was involved in regulating muscle glucose metabolism in recovery from exercise. The findings support that exercise-induced activation of the AMPKγ3 complex in human and mouse skeletal muscle enhances glucose uptake in recovery from exercise via increased translocation of GLUT4 to the plasma membrane. This work uncovers the physiological role of the AMPKγ3 complex in regulating muscle glucose uptake that favors replenishment of the muscle cellular energy stores.

Dynamic remodeling of Escherichia coli interactome in response to environmental perturbations.

Proteins play an essential role in the vital biological processes governing cellular functions. Most proteins function as members of macromolecular machines, with the network of interacting proteins revealing the molecular mechanisms driving the formation of these complexes. Profiling the physiology-driven remodeling of these interactions within different contexts constitutes a crucial component to achieving a comprehensive systems-level understanding of interactome dynamics. Here, we apply co-fractionation mass spectrometry and computational modeling to quantify and profile the interactions of ∼2000 proteins in the bacterium Escherichia coli cultured under 10 distinct culture conditions. The resulting quantitative co-elution patterns revealed large-scale condition-dependent interaction remodeling among protein complexes involved in diverse biochemical pathways in response to the unique environmental challenges. The network-level analysis highlighted interactome-wide biophysical properties and structural patterns governing interaction remodeling. Our results provide evidence of the local and global plasticity of the E. coli interactome along with a rigorous generalizable framework to define protein interaction specificity. We provide an accompanying interactive web application to facilitate the exploration of these rewired networks.

Development and mechanistic investigation of the dehydrogenation of alcohols with an iron(III) salen catalyst.

The iron(III) salen complex (R,R)-N,N'-bis(salicylidene)-1,2-cyclohexanediamineiron(III) chloride has been developed as a catalyst for the acceptorless dehydrogenation of alcohols. The complex catalyzes the direct synthesis of imines in good yields from different primary alcohols and amines with the liberation of hydrogen gas. The mechanism has been investigated experimentally with labelled substrates and theoretically with density functional theory calculations. In contrast to the corresponding manganese(III) salen-catalyzed dehydrogenation, it has not been possible to identify a homogeneous catalytic pathway with the iron complex. Instead, poisoning experiments with trimethylphosphine and mercury indicated that the catalytically active species are heterogeneous small iron particles.

Custom-made triflanged implants in reconstruction of severe acetabular bone loss with pelvic discontinuity after total hip arthroplasty consecutive cohort study : two to 11 years of follow-up.

AIMS: Pelvic discontinuity is a rare but increasingly common complication of total hip arthroplasty (THA). This single-centre study evaluated the performance of custom-made triflange acetabular components in acetabular reconstruction with pelvic discontinuity by determining: 1) revision and overall implant survival rates; 2) discontinuity healing rate; and 3) Harris Hip Score (HHS). METHODS: Retrospectively collected data of 38 patients (39 hips) with pelvic discontinuity treated with revision THA using a custom-made triflange acetabular component were analyzed. Minimum follow-up was two years (mean 5.1 years (2 to 11)). RESULTS: There were eight subsequent surgical interventions. Two failures (5%) of the triflange acetabular components were both revised because of deep infection. There were seven (18%) patients with dislocation, and five (13%) of these were treated with a constraint liner. One patient had a debridement, antibiotics, and implant retention (DAIR) procedure. In 34 (92%) hips the custom-made triflange component was considered stable, with a healed pelvic discontinuity with no aseptic loosening at midterm follow-up. Mean HHS was 80.5 (48 to 96). CONCLUSION: The performance of the custom triflange implant in this study is encouraging, with high rates of discontinuity healing and osteointegration of the acetabular implant with no aseptic loosening at midterm follow-up. However, complications are not uncommon, particularly instability which we successfully addressed with constrained liners.Cite this article: Bone Jt Open 2022;3(11):867-876.

CD49b identifies functionally and epigenetically distinct subsets of lineage-biased hematopoietic stem cells.

Hematopoiesis is maintained by functionally diverse lineage-biased hematopoietic stem cells (HSCs). The functional significance of HSC heterogeneity and the regulatory mechanisms underlying lineage bias are not well understood. However, absolute purification of HSC subtypes with a pre-determined behavior remains challenging, highlighting the importance of continued efforts toward prospective isolation of homogeneous HSC subsets. In this study, we demonstrate that CD49b subdivides the most primitive HSC compartment into functionally distinct subtypes: CD49b- HSCs are highly enriched for myeloid-biased and the most durable cells, while CD49b+ HSCs are enriched for multipotent cells with lymphoid bias and reduced self-renewal ability. We further demonstrate considerable transcriptional similarities between CD49b- and CD49b+ HSCs but distinct differences in chromatin accessibility. Our studies highlight the diversity of HSC functional behaviors and provide insights into the molecular regulation of HSC heterogeneity through transcriptional and epigenetic mechanisms.

Thymus Functionality Needs More Than a Few TECs.

The thymus, a primary lymphoid organ, produces the T cells of the immune system. Originating from the 3rd pharyngeal pouch during embryogenesis, this organ functions throughout life. Yet, thymopoiesis can be transiently or permanently damaged contingent on the types of systemic stresses encountered. The thymus also undergoes a functional decline during aging, resulting in a progressive reduction in naïve T cell output. This atrophy is evidenced by a deteriorating thymic microenvironment, including, but not limited, epithelial-to-mesenchymal transitions, fibrosis and adipogenesis. An exploration of cellular changes in the thymus at various stages of life, including mouse models of in-born errors of immunity and with single cell RNA sequencing, is revealing an expanding number of distinct cell types influencing thymus functions. The thymus microenvironment, established through interactions between immature and mature thymocytes with thymus epithelial cells (TEC), is well known. Less well appreciated are the contributions of neural crest cell-derived mesenchymal cells, endothelial cells, diverse hematopoietic cell populations, adipocytes, and fibroblasts in the thymic microenvironment. In the current review, we will explore the contributions of the many stromal cell types participating in the formation, expansion, and contraction of the thymus under normal and pathophysiological processes. Such information will better inform approaches for restoring thymus functionality, including thymus organoid technologies, beneficial when an individuals' own tissue is congenitally, clinically, or accidentally rendered non-functional.

Small RNAs Asserting Big Roles in Mycobacteria.

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb), with 10.4 million new cases per year reported in the human population. Recent studies on the Mtb transcriptome have revealed the abundance of noncoding RNAs expressed at various phases of mycobacteria growth, in culture, in infected mammalian cells, and in patients. Among these noncoding RNAs are both small RNAs (sRNAs) between 50 and 350 nts in length and smaller RNAs (sncRNA) < 50 nts. In this review, we provide an up-to-date synopsis of the identification, designation, and function of these Mtb-encoded sRNAs and sncRNAs. The methodological advances including RNA sequencing strategies, small RNA antagonists, and locked nucleic acid sequence-specific RNA probes advancing the studies on these small RNA are described. Initial insights into the regulation of the small RNA expression and putative processing enzymes required for their synthesis and function are discussed. There are many open questions remaining about the biological and pathogenic roles of these small non-coding RNAs, and potential research directions needed to define the role of these mycobacterial noncoding RNAs are summarized.

Genome-Scale Reconstruction of Microbial Dynamic Phenotype: Successes and Challenges.

This review is a part of the SI 'Genome-Scale Modeling of Microorganisms in the Real World'. The goal of GEM is the accurate prediction of the phenotype from its respective genotype under specified environmental conditions. This review focuses on the dynamic phenotype; prediction of the real-life behaviors of microorganisms, such as cell proliferation, dormancy, and mortality; balanced and unbalanced growth; steady-state and transient processes; primary and secondary metabolism; stress responses; etc. Constraint-based metabolic reconstructions were successfully started two decades ago as FBA, followed by more advanced models, but this review starts from the earlier nongenomic predecessors to show that some GEMs inherited the outdated biokinetic frameworks compromising their performances. The most essential deficiencies are: (i) an inadequate account of environmental conditions, such as various degrees of nutrients limitation and other factors shaping phenotypes; (ii) a failure to simulate the adaptive changes of MMCC (MacroMolecular Cell Composition) in response to the fluctuating environment; (iii) the misinterpretation of the SGR (Specific Growth Rate) as either a fixed constant parameter of the model or independent factor affecting the conditional expression of macromolecules; (iv) neglecting stress resistance as an important objective function; and (v) inefficient experimental verification of GEM against simple growth (constant MMCC and SGR) data. Finally, we propose several ways to improve GEMs, such as replacing the outdated Monod equation with the SCM (Synthetic Chemostat Model) that establishes the quantitative relationships between primary and secondary metabolism, growth rate and stress resistance, process kinetics, and cell composition.

Incorporation of a Poly-ε-Caprolactone Scaffold in a ;Circular Stapled End-To-End Small Intestine Anastomosis Does Not Have Any Adverse Effects Within 30 days: A Study in Piglets.

Background. Incorporation of a poly-ε-caprolactone (PCL) scaffold in circular stapled anastomoses has been shown to increase the anastomotic tensile strength on postoperative day (POD) 5 in a pig model. The aim of this study was to investigate the effects of incorporation of a PCL scaffold in a circular stapled end-to-end small intestine anastomosis, with stricture formation and anastomotic histology as primary outcomes in a 30-day observation period. Methods. A total of 15 piglets were included. In each piglet, three circular stapled end-to-end anastomoses were made in the small intestines. Two were interventional and one was a control. On POD 10, 20, or 30, the anastomoses were subjected to in vivo intraluminal contrast study, and the index for anastomotic lumen was calculated. The anastomotic segment was resected and subjected to a tensile strength test and histological examination. Results. At POD 10, the mean ± SD value for anastomotic index was .749 ± .065 in control anastomoses and .637 ± .051 in interventional anastomosis (P = .0046), at POD 20, .541 ± .150 and .724 ± .07 (P = .051), and at POD 30, .645 ± .103 and .686 ± .057 (P = .341), respectively. No significant difference was observed in maximum tensile strength and histology at POD 30. Conclusions. The incorporation of a PCL scaffold in a circular stapled end-to-end small intestine anastomosis does not increase the risk of stricture or impair wound healing after 30 days.

Serum IgG Profiling of Toddlers Reveals a Subgroup with Elevated Seropositive Antibodies to Viruses Correlating with Increased Vaccine and Autoantigen Responses.

PURPOSE: The human antibody repertoire forms in response to infections, the microbiome, vaccinations, and environmental exposures. The specificity of such antibody responses was compared among a cohort of toddlers to identify differences between seropositive versus seronegative responses. METHODS: An assessment of the serum IgM and IgG antibody reactivities in 197 toddlers of 1- and 2-years of age was performed with a microfluidic array containing 110 distinct antigens. Longitudinal profiling was done from years 1 to 2. Seropositivity to RNA and DNA viruses; bacteria; live attenuated, inactive, and subunit vaccines; and autoantigens was compared. A stratification was developed based on quantitative variations in the IgG responses. Clinical presentations and previously known genetic risk alleles for various immune system conditions were investigated in relation to IgG responses. RESULTS: IgG reactivities stratified toddlers into low, moderate, and high responder groups. The high group (17%) had elevated IgG responses to multiple RNA and DNA viruses (e.g., respiratory syncytial virus, Epstein-Barr virus, adenovirus, Coxsackievirus) and this correlated with increased responses to live attenuated viral vaccines and certain autoantigens. This high group was more likely to be associated with gestational diabetes and an older age. Genetic analyses identified polymorphisms in the IL2RB, TNFSF4, and INS genes in two high responder individuals that were associated with their elevated cytokine levels and clinical history of eczema and asthma. CONCLUSION: Serum IgG profiling of toddlers reveals correlations between the magnitude of the antibody responses towards viruses, live attenuated vaccines, and certain autoantigens. A low responder group had much weaker responses overall, including against vaccines. The serum antibody screen also identifies individuals with IgG responses to less common infections (West Nile virus, parvovirus, tuberculosis). The characterization of the antibody responses in combination with the identification of genetic risk alleles provides an opportunity to identify children with increased risk of clinical disease.

SARS-CoV-2 infection associated with hepatitis in an infant with X-linked severe combined immunodeficiency.

X-linked severe combined immunodeficiency (X-SCID) is a disorder of adaptive immunity caused by mutations in the IL-2 receptor common gamma chain gene resulting in deficiencies of T and natural killer cells, coupled with severe dysfunction in B cells. X-SCID is lethal without allogeneic stem cell transplant or gene therapy due to opportunistic infections. An infant with X-SCID became infected with SARS-CoV-2 while awaiting transplant. The patient developed severe hepatitis without the respiratory symptoms typical of COVID-19. He was treated with convalescent plasma, and thereafter was confirmed to have SARS-CoV-2 specific antibodies, as detected with a microfluidic antigen array. After resolution of the hepatitis, he received a haploidentical CD34 selected stem cell transplant, without conditioning, from his father who had recovered from COVID-19. SARS CoV-2 was detected via RT-PCR on nasopharyngeal swabs until 61 days post transplantation. He successfully engrafted donor T and NK cells, and continues to do well clinically.

True and Illusory Benefits of Modeling: Comment on "Genome-Scale Metabolic Network Reconstruction and In Silico Analysis of Hexanoic Acid Producing Megasphaera elsdenii. Microorganisms 2020, 8, 539".

Lee et al. [1] recently published a paper that is part of the special issue "Genome-Scale Modeling of Microorganisms in the Real World"[...].

sncRNA-1 Is a Small Noncoding RNA Produced by Mycobacterium tuberculosis in Infected Cells That Positively Regulates Genes Coupled to Oleic Acid Biosynthesis.

Nearly one third of the world's population is infected with Mycobacterium tuberculosis (Mtb). While much work has focused on the role of different Mtb encoded proteins in pathogenesis, recent studies have revealed that Mtb also transcribes many noncoding RNAs whose functions remain poorly characterized. We performed RNA sequencing and identified a subset of Mtb H37Rv-encoded small RNAs (<30 nts in length) that were produced in infected macrophages. Designated as smaller noncoding RNAs (sncRNAs), three of these predominated the read counts. Each of the three, sncRNA-1, sncRNA-6, and sncRNA-8 had surrounding sequences with predicted stable secondary RNA stem loops. Site-directed mutagenesis of the precursor sequences suggest the existence of a hairpin loop dependent RNA processing mechanism. A functional assessment of sncRNA-1 suggested that it positively regulated two mycobacterial transcripts involved in oleic acid biosynthesis. Complementary loss- and gain- of-function approaches revealed that sncRNA-1 positively supports Mtb growth and survival in nutrient-depleted cultures as well as in infected macrophages. Overall, the findings reveal that Mtb produces sncRNAs in infected cells, with sncRNA-1 modulating mycobacterial gene expression including genes coupled to oleic acid biogenesis.

Molecular Insights Into the Causes of Human Thymic Hypoplasia With Animal Models.

22q11.2 deletion syndrome (DiGeorge), CHARGE syndrome, Nude/SCID and otofaciocervical syndrome type 2 (OTFCS2) are distinct clinical conditions in humans that can result in hypoplasia and occasionally, aplasia of the thymus. Thymic hypoplasia/aplasia is first suggested by absence or significantly reduced numbers of recent thymic emigrants, revealed in standard-of-care newborn screens for T cell receptor excision circles (TRECs). Subsequent clinical assessments will often indicate whether genetic mutations are causal to the low T cell output from the thymus. However, the molecular mechanisms leading to the thymic hypoplasia/aplasia in diverse human syndromes are not fully understood, partly because the problems of the thymus originate during embryogenesis. Rodent and Zebrafish models of these clinical syndromes have been used to better define the underlying basis of the clinical presentations. Results from these animal models are uncovering contributions of different cell types in the specification, differentiation, and expansion of the thymus. Cell populations such as epithelial cells, mesenchymal cells, endothelial cells, and thymocytes are variably affected depending on the human syndrome responsible for the thymic hypoplasia. In the current review, findings from the diverse animal models will be described in relation to the clinical phenotypes. Importantly, these results are suggesting new strategies for regenerating thymic tissue in patients with distinct congenital disorders.

Abdominal fat distribution measured by ultrasound and aerobic fitness in young Danish men born with low and normal birth weight.

Abdominal subcutaneous and visceral adipose tissue thickness was examined by ultrasound in 17 men with low birth weight (LBW) and 26 with normal BW control individuals to determine if abdominal obesity in LBW individuals is due to increased visceral or subcutaneous fat mass/thickness, or both. Men born with LBW had an increased waist-to-hip ratio (P = 0.04), greater abdominal fat thickness (P = 0.05) and increased visceral (VAT) and subcutaneous adipose tissue (SAT) thickness compared with controls, however the latter not statistically significant (P = 0.08, P = 0.10). A significant difference between birth weight groups in both SAT (P = 0.04) and VAT (P = 0.03) was found after adjustment for weight, whereas no significant difference in either SAT (P = 0.93) or VAT (P = 0.30) was found after adjustment for BMI. Increased waist-to-hip ratio in LBW individuals is due to increased total abdominal fat including both subcutaneous and visceral fat.