tbuckley/cabot-search huggingface dataset:
Treatment of Highly Drug-Resistant Pulmonary Tuberculosis
Authors: Mathieu S Bolhuis, Tjip S van der Werf, Onno W Akkerman
Journal: New England Journal of Medicine (2020)

BACKGROUND Patients with highly drug-resistant forms of tuberculosis have limited treatment options and historically have had poor outcomes. METHODS In an open-label, single-group study in which follow-up is ongoing at three South African sites, we investigated treatment with three oral drugs - bedaquiline, pretomanid, and linezolid - that have bactericidal activity against tuberculosis and to which there is little preexisting resistance. We evaluated the safety and efficacy of the drug combination for 26 weeks in patients with extensively drug-resistant tuberculosis and patients with multidrug-resistant tuberculosis that was not responsive to treatment or for which a second-line regimen had been discontinued because of side effects. The primary end point was the incidence of an unfavorable outcome, defined as treatment failure (bacteriologic or clinical) or relapse during follow-up, which continued until 6 months after the end of treatment. Patients were classified as having a favorable outcome at 6 months if they had resolution of clinical disease, a negative culture status, and had not already been classified as having had an unfavorable outcome. Other efficacy end points and safety were also evaluated. RESULTS A total of 109 patients were enrolled in the study and were included in the evaluation of efficacy and safety end points. At 6 months after the end of treatment in the intention-to-treat analysis, 11 patients (10%) had an unfavorable outcome and 98 patients (90%; 95% confidence interval, 83 to 95) had a favorable outcome. The 11 unfavorable outcomes were 7 deaths (6 during treatment and 1 from an unknown cause during follow-up), 1 withdrawal of consent during treatment, 2 relapses during follow-up, and 1 loss to follow-up. The expected linezolid toxic effects of peripheral neuropathy (occurring in 81% of patients) and myelosuppression (48%), although common, were manageable, often leading to dose reductions or interruptions in treatment with linezolid. CONCLUSIONS The combination of bedaquiline, pretomanid, and linezolid led to a favorable outcome at 6 months after the end of therapy in a high percentage of patients with highly drug-resistant forms of tuberculosis; some associated toxic effects were observed. (Funded by the TB Alliance and others; ClinicalTrials.gov number, NCT02333799.).
Model-Based Inference of Punctuated Molecular Evolution
Authors: Marc Manceau, Julie Marin, Hélène Morlon, Amaury Lambert
Journal: Molecular Biology and Evolution (2020)

Abstract In standard models of molecular evolution, DNA sequences evolve through asynchronous substitutions according to Poisson processes with a constant rate (called the molecular clock) or a rate that can vary (relaxed clock). However, DNA sequences can also undergo episodes of fast divergence that will appear as synchronous substitutions affecting several sites simultaneously at the macroevolutionary timescale. Here, we develop a model, which we call the Relaxed Clock with Spikes model, combining basal, clock-like molecular substitutions with episodes of fast divergence called spikes arising at speciation events. Given a multiple sequence alignment and its time-calibrated species phylogeny, our model is able to detect speciation events (including hidden ones) cooccurring with spike events and to estimate the probability and amplitude of these spikes on the phylogeny. We identify the conditions under which spikes can be distinguished from the natural variance of the clock-like component of molecular substitutions and from variations of the clock. We apply the method to genes underlying snake venom proteins and identify several spikes at gene-specific locations in the phylogeny. This work should pave the way for analyses relying on whole genomes to inform on modes of species diversification.
Sex-dependent calcium hyperactivity due to lysosomal-related dysfunction in astrocytes from APOE4 versus APOE3 gene targeted replacement mice
Authors: Raquel Larramona-Arcas, Candela González-Arias, Gertrudis Perea, Antonia Gutiérrez, Javier Vitorica, Tamara García-Barrera, José Luis Gómez-Ariza, Raquel Pascua-Maestro, María Dolores Ganfornina, Eleanna Kara, Eloise Hudry, Marta Martinez-Vicente, Miquel Vila, Elena Galea, Roser Masgrau
Journal: Molecular Neurodegeneration (2020)

The apolipoprotein E (APOE) gene exists in three isoforms in humans: APOE2, APOE3 and APOE4. APOE4 causes structural and functional alterations in normal brains, and is the strongest genetic risk factor of the sporadic form of Alzheimer's disease (LOAD). Research on APOE4 has mainly focused on the neuronal damage caused by defective cholesterol transport and exacerbated amyloid-β and Tau pathology. The impact of APOE4 on non-neuronal cell functions has been overlooked. Astrocytes, the main producers of ApoE in the healthy brain, are building blocks of neural circuits, and Ca2+ signaling is the basis of their excitability. Because APOE4 modifies membrane-lipid composition, and lipids regulate Ca2+ channels, we determined whether APOE4 dysregulates Ca2+signaling in astrocytes.Ca2+ signals were recorded in astrocytes in hippocampal slices from APOE3 and APOE4 gene targeted replacement male and female mice using Ca2+ imaging. Mechanistic analyses were performed in immortalized astrocytes. Ca2+ fluxes were examined with pharmacological tools and Ca2+ probes. APOE3 and APOE4 expression was manipulated with GFP-APOE vectors and APOE siRNA. Lipidomics of lysosomal and whole-membranes were also performed.We found potentiation of ATP-elicited Ca2+responses in APOE4 versus APOE3 astrocytes in male, but not female, mice. The immortalized astrocytes modeled the male response, and showed that Ca2+ hyperactivity associated with APOE4 is caused by dysregulation of Ca2+ handling in lysosomal-enriched acidic stores, and is reversed by the expression of APOE3, but not of APOE4, pointing to loss of function due to APOE4 malfunction. Moreover, immortalized APOE4 astrocytes are refractory to control of Ca2+ fluxes by extracellular lipids, and present distinct lipid composition in lysosomal and plasma membranes.Immortalized APOE4 versus APOE3 astrocytes present: increased Ca2+ excitability due to lysosome dysregulation, altered membrane lipidomes and intracellular cholesterol distribution, and impaired modulation of Ca2+ responses upon changes in extracellular lipids. Ca2+ hyperactivity associated with APOE4 is found in astrocytes from male, but not female, targeted replacement mice. The study suggests that, independently of Aβ and Tau pathologies, altered astrocyte excitability might contribute to neural-circuit hyperactivity depending on APOE allele, sex and lipids, and supports lysosome-targeted therapies to rescue APOE4 phenotypes in LOAD.
Point-of-Care Devices to Detect Zika and Other Emerging Viruses
Authors: Helena de Puig, Irene Bosch, James J. Collins, Lee Gehrke
Journal: Annual Review of Biomedical Engineering (2020)

Rapid diagnostic tests (point-of-care devices) are critical components of informed patient care and public health monitoring (surveillance applications). We propose that among the many rapid diagnostics platforms that have been tested or are in development, lateral flow immunoassays and synthetic biology–based diagnostics (including CRISPR-based diagnostics) represent the best overall options given their ease of use, scalability for manufacturing, sensitivity, and specificity. This review describes the identification of lateral flow immunoassay monoclonal antibody pairs that detect and distinguish between closely related pathogens and that are used in combination with functionalized multicolored nanoparticles and computational methods to deconvolute data. We also highlight the promise of synthetic biology–based diagnostic tests, which use synthetic genetic circuits that activate upon recognition of a pathogen-associated nucleic acid sequence, and discuss how the combined or parallel use of lateral flow immunoassays and synthetic biology tools may represent the future of scalable rapid diagnostics.
Harry John Espiner: medical innovator who invented the Espiner bag
Authors: Matt Limb
Journal: BMJ (2020)

Harry Espiner was a distinguished surgeon, researcher, lecturer, and medical innovator who also designed equipment used by surgeons worldwide. He performed some of the earliest laparoscopic surgery in the UK and developed a special retrieval sac, the Espiner bag, used in keyhole operations such as gallbladder removal. He was always “pushing at the frontiers of innovation,” say colleagues, having also initiated research into the harmful effects of starch powder used in surgical gloves.

Espiner, a New Zealander, arrived in the UK in the late 1950s as a well regarded surgical trainee and went on to have a distinguished career as a consultant surgeon at Bristol Royal Infirmary and lecturer at the University of Bristol. He became a pioneer in laparoscopic cholecystectomy and “one of the very first surgeons to take on the new technique in the south west region,” says Alan Roe, who worked with him as a senior registrar and co-researcher. He was also among the first in the world to remove a cancerous tumour of the colon solely by minimal …
Screening for Anxiety in Adolescent and Adult Women: A Recommendation From the Women's Preventive Services Initiative
Authors: Kimberly D. Gregory, David Chelmow, Heidi D. Nelson, Maureen Sayres Van Niel, Jeanne A. Conry, Francisco Garcia, Susan M. Kendig, Nancy O'Reilly, Amir Qaseem, Diana Ramos, Alina Salganicoff, Sarah Son, Julie K. Wood, Christopher Zahn
Journal: Annals of Internal Medicine (2020)

The Women's Preventive Services Initiative (WPSI), a national coalition of women's health professional organizations and patient representatives, developed a recommendation on screening for anxiety in adolescent and adult women to improve detection; achieve earlier diagnosis and treatment; and improve health, function, and well-being. The WPSI's recommendations are intended to guide clinical practice and coverage of services for the Health Resources and Services Administration and other stakeholders. The target audience for this recommendation includes all clinicians providing preventive health care to women, particularly in primary care settings. This recommendation applies to women and adolescent girls aged 13 years or older who are not currently diagnosed with anxiety disorders, including pregnant and postpartum women.The WPSI developed this recommendation after evaluating results of a systematic review of the effectiveness of screening, accuracy of screening instruments, and benefits and harms of treatments in adolescent girls and adult women. No studies directly evaluated the overall effectiveness or harms of screening for anxiety. Twenty-seven screening instruments and their variations were moderately to highly accurate in identifying anxiety (33 individual studies and 2 systematic reviews; 171 studies total). Symptoms improved and relapse rates decreased with psychological therapies (246 randomized controlled trials [RCTs] in 5 systematic reviews) and with selective serotonin reuptake inhibitors or selective serotonin and norepinephrine reuptake inhibitors (126 RCTs in 3 systematic reviews). The WPSI also considered the effect of screening on symptom progression and identification of associated and underlying conditions, as well as implementation factors.The WPSI recommends screening for anxiety in women and adolescent girls aged 13 years or older who are not currently diagnosed with anxiety disorders, including pregnant and postpartum women. Optimal screening intervals are unknown, and clinical judgment should be used to determine frequency. When screening suggests the presence of anxiety, further evaluation is necessary to establish the diagnosis and determine appropriate treatment and follow-up.
Abstract 9773: Outcomes of Cancer Patients Undergoing Percutaneous Pericardiocentesis for Pericardial Effusion
Authors: Danielle El Haddad
Journal: Circulation (2015)

Objectives: We evaluated outcomes of cancer patients undergoing percutaneous pericardiocentesis for pericardial effusion and assessed the procedure’s safety in patients with thrombocytopenia. Background: Pericardial effusion is common in cancer patients. The optimal therapeutic approach is not well defined and in practice depends on patient characteristics and local hospital expertise. Percutaneous pericardiocentesis is less invasive than surgery, but its effectiveness and safety are not well documented. Methods: Cancer patients who underwent percutaneous pericardiocentesis for pericardial effusion between November 2009 and October 2014 at MD Anderson Cancer Center were included. Procedure-related complications, effusion recurrence rate, and overall survival were analyzed. Results: Of 1645 cancer patients referred for pericardial effusion, 212 (13%) underwent percutaneous pericardiocentesis; procedure was successful in 99% of the cases, and there were no procedure-related deaths. Four patients had major procedure-related bleeding necessitating blood transfusions and/or surgical intervention. Procedure-related bleeding did not differ between patients with normal platelet counts and thrombocytopenic patients. Effusion recurred in 26 (12%) patients. Patients with catheter drainage for 3-5 days had the lowest recurrence rate (10%). Median overall survival was 143 days (95% CI, 95-221). Age&gt;65 years, lung cancer, platelet count &lt;20,000/μL, and malignant pericardial fluid were independently associated with poor prognosis. In lung cancer, but not breast cancer, median survival was shorter in patients with malignant effusions than in those with nonmalignant effusions. Conclusion: Percutaneous pericardiocentesis with extended catheter drainage, as primary treatment for pericardial effusion in cancer patients, is safe and effective, including in those with thrombocytopenia. Malignant pericardial effusion significantly shortens the survival outcome of lung cancer patients, but not breast cancer patients.
Efficacy and safety of omalizumab in nasal polyposis: 2 randomized phase 3 trials
Authors: Philippe Gevaert, Theodore A. Omachi, Jonathan Corren, Joaquim Mullol, Joseph Han, Stella E. Lee, Derrick Kaufman, Monica Ligueros-Saylan, Monet Howard, Rui Zhu, Ryan Owen, Kit Wong, Lutaf Islam, Claus Bachert
Journal: Journal of Allergy and Clinical Immunology (2020)

Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by IgE hyperproduction and eosinophilic inflammation. The anti-IgE antibody, omalizumab, has demonstrated efficacy in patients with CRSwNP and comorbid asthma previously.Our aim was to determine omalizumab safety and efficacy in CRSwNP in phase 3 trials (POLYP 1 and POLYP 2).Adults with CRSwNP with inadequate response to intranasal corticosteroids were randomized (1:1) to omalizumab or placebo and intranasal mometasone for 24 weeks. Coprimary end points included change from baseline to week 24 in Nasal Polyp Score (NPS) and Nasal Congestion Score. Secondary end points included change from baseline to week 24 in Sino-Nasal Outcome Test-22 (SNOT-22) score, University of Pennsylvania Smell Identification Test, sense of smell, postnasal drip, runny nose, and adverse events.Patients in POLYP 1 (n = 138) and POLYP 2 (n = 127) exhibited severe CRSwNP and substantial quality of life impairment evidenced by a mean NPS higher than 6 and SNOT-22 score of approximately 60. Both studies met both the coprimary end points. SNOT-22 score, University of Pennsylvania Smell Identification Test score, sense of smell, postnasal drip, and runny nose were also significantly improved for omalizumab versus placebo. In POLYP 1 and POLYP 2, the mean changes from baseline at week 24 for omalizumab versus placebo were as follows: NPS, -1.08 versus 0.06 (P < .0001) and -0.90 versus -0.31 (P = .0140); Nasal Congestion Score, -0.89 versus -0.35 (P = .0004) and -0.70 versus -0.20 (P = .0017); and SNOT-22 score, -24.7 versus -8.6 (P < .0001) and -21.6 versus -6.6 (P < .0001). Adverse events were similar between groups.Omalizumab significantly improved endoscopic, clinical, and patient-reported outcomes in severe CRSwNP with inadequate response to intranasal corticosteroids, and it was well tolerated.
Response to: ‘Monitoring of patients with systemic lupus erythematosus during the COVID-19 outbreak’ by Holubar <i>et al</i>
Authors: Alexis Mathian, Zahir Amoura
Journal: Annals of the Rheumatic Diseases (2020)

We thank Holubar et al for their interest in our study reporting on the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease 2019 (COVID-19) in a case series of patients with systemic lupus erythematosus (SLE) under long-term treatment with hydroxychloroquine.1 2 Their results showing a low incidence of symptoms of viral infections in a population of patients with SLE corroborates those from Favalli et al ,3 suggesting that the impact of COVID-19 in patients with SLE is rather low. However, as acknowledged by Holubar et al , the prevalence of COVID-19 in the general population is very low as well, and even lower in regions, such as Occitanie in Southern France where the study of Holubar et al was carried out between 1 February and 24 April.1 2 By 11 May, Salje et al estimated that …
Integration of metagenomics‐metabolomics reveals specific signatures and functions of airway microbiota in mite‐sensitized childhood asthma
Authors: Chih‐Yung Chiu, Hsin‐Cheng Chou, Lun‐Ching Chang, Wen‐Lang Fan, Michael Cong Vinh Dinh, Yu‐Lun Kuo, Wen‐Hung Chung, Hsin‐Chih Lai, Wen‐Ping Hsieh, Shih‐Chi Su
Journal: Allergy (2020)

Childhood asthma is a multifactorial inflammatory condition of the airways, associated with specific changes in respiratory microbiome and circulating metabolome.To explore the functional capacity of asthmatic microbiome and its intricate connection with the host, we performed shotgun sequencing of airway microbiome and untargeted metabolomics profiling of serum samples in a cohort of children with mite-sensitized asthma and non-asthmatic controls.We observed higher gene counts and sample-to-sample dissimilarities in asthmatic microbiomes, indicating a more heterogeneous community structure and functionality among the cases than in controls. Moreover, we identified airway microbial species linked to changes in circulating metabolites and IgE responses of the host, including a positive correlation between Prevotella sp oral taxon 306 and dimethylglycine that were both decreased in patients. Several control-enriched species (Eubacterium sulci, Prevotella pallens, and Prevotella sp oral taxon 306) were inversely correlated with total and allergen-specific IgE levels. Genes related to microbial carbohydrate, amino acid, and lipid metabolism were differentially enriched, suggesting that changes in microbial metabolism may contribute to respiratory health in asthmatics. Pathway modules relevant to allergic responses were differentially abundant in asthmatic microbiome, such as enrichments for biofilm formation by Pseudomonas aeruginosa, membrane trafficking, histidine metabolism, and glycosaminoglycan degradation, and depletions for polycyclic aromatic hydrocarbon degradation. Further, we identified metagenomic and metabolomic markers (eg, Eubacterium sulci) to discriminate cases from the non-asthmatic controls.Our dual-omics data reveal the connections between respiratory microbes and circulating metabolites perturbed in mite-sensitized pediatric asthma, which may be of etiological and diagnostic implications.
AB0393 EFFICACY OF HYDROXYCHLOROQUINE FOR LUPUS NEPHRITIS IN MAINTENANCE PHASE
Authors: M. Watanabe, Y. Haji, M. Kato, T. Ito, Y. Banno, M. Okada
Journal: Annals of the Rheumatic Diseases (2020)

Background: Hydroxychloroquine (HCQ) is an essential drug for systemic lupus erythematosus. But in Japan, chloroquine and HCQ remain unavailable until mid 2015 because of a series of lawsuits about its retinal toxicity in the 1970s. There is insufficient knowledge regarding renal protective effect of HCQ. Objectives: We aimed to investigate its efficacy of adding HCQ for Lupus nephritis (LN) as a maintenance-phase therapy. Methods: We conducted an observational retrospective cohort study included patients with LN (n=42) in maintenance-phase in Japan. We reviewed medical records of LN patients aged &gt; 18 years who were initiated HCQ from May 2015 to May 2018. Maintenance phase was defined as stabilization in serum creatinine and urinary segment after induction therapy and who achieved complete or partial remission. The annual change of proteinuria was compared between patients on HCQ who have proteinuria (&gt;0.5g/gCr) or not. Other outcome measures were disease flare, dose of steroids, renal and immunologic features. Results: A total of 42 patients were analyzed and allocated to two groups based on their amount of daily urine protein level: HCQ with proteinuria as group A (&gt;0.5g/gCr, n=14) and HCQ without proteinuria as group B(≦0.5g/gCr, n=28). Both groups were comparable, with mean (SD) age of 36.1 (12.9) years and 37.5 (13.8), female 78.6% and 92.9% in each group, mean (SD) disease duration until HCQ of 3.5 (3.25) and 3.3 (2.9) years in group A and group B, with prednisolone dose at base line of 10.3 (7.1) mg and 7.9 (4.4) mg, respectively. The mean (SD) proteinuria at base line was 1.38 (1.11) g/gCr in group A and 0.20 (0.09) g/gCr in group B and after 12 months, proteinuria decreased in group A (-1.34 g/gCr in group A vs +0.03 g/gCr in group B; p&lt;.001;95% CI,0.305-0.736). No relapse was experienced in group A during the study period. Conclusion: In patients with clinically stable LN but with proteinuria, hydroxychloroquine is a good therapeutic option for achievement of complete remission. Disclosure of Interests: None declared
Increased Helicobacter felis colonization in male 129/Sv mice fails to suppress gastritis (vol 2, pg 358, 2011)
Authors: Garrett Z Ng, Alison L Every, Michael A McGuckin, Philip Sutton
Journal: Gut Microbes (2011)

Development of the pathologies associated with Helicobacter pylori infection, most seriously gastric adenocarcinoma, are a consequence of chronic inflammation, which both host and pathogen go to some lengths to minimize. Recently, we presented evidence that H. pylori can suppress the development of inflammation in its immediate microenvironment in the gastric mucosa of 129/Sv mice. We have now extended this study by showing that H. felis, a gastric colonizing Helicobacter closely related to H. pylori, does not possess the same ability to suppress Helicobacter-induced gastritis in mice. Differences between these bacterial species may provide clues as to the mechanism behind the inflammation-regulating ability of H. pylori. Moreover, our demonstration that H. pylori but not H. felis can locally suppress inflammation in vivo may explain why H. felis infection induces superior levels of gastritis as compared with H. pylori infection of mice.
Reply to Mutlu Ates and Yigit Akin’s Letter to the Editor re: Giuseppe Simone, Umberto Anceschi, Gabriele Tuderti, et al. Robot-assisted Partial Adrenalectomy for the Treatment of Conn’s Syndrome: Surgical Technique, and Perioperative and Functional Outcomes. Eur Urol 2019;75:811–6
Authors: Umberto Anceschi, Giuseppe Simone
Journal: European Urology (2020)