Breastfeeding in mothers with systemic lupus erythematosus.

INTRODUCTION: Breastfeeding is known to improve the well-being of a mother and her infant, and about half of all new mothers breastfeed, but it is unknown how breastfeeding is pursued in systemic lupus erythematosus (SLE; lupus) patients. We sought to determine the rate of breastfeeding and the factors influencing this among women with lupus. In addition, we reassessed the current safety data in lactation of lupus medications. METHODS: Data were collected from lupus patients enrolled in a prospective registry who fulfilled the 2012 SLICC criteria, had a live birth, and for whom postpartum breastfeeding status was known. Data included physician assessments of lupus activity and medications, breastfeeding intentions during pregnancy and practice following pregnancy. The safety of medications in breastfed infants was assessed through a comprehensive review of LactMed, a national database about medications in lactation. RESULTS: A total of 51 pregnancies in 84 women with lupus were included in the study. Half of the lupus patients (n = 25, 49%) chose to breastfeed. The rate of breastfeeding was not significantly affected by socioeconomic factors. In contrast, low postpartum lupus activity, term delivery, and a plan to breastfeed early in pregnancy were significantly associated with breastfeeding in lupus patients. In reviewing the most up-to-date data, the majority of lupus medications appear to have very minimal transfer into breast milk and are likely compatible with breastfeeding. CONCLUSION: Half of women with lupus breastfed and most desire to breastfeed. Hydroxychloroquine, azathioprine, methotrexate, and prednisone have very limited transfer into breast milk and may be continued while breastfeeding.

High-flow nasal oxygen in resource-constrained, non-intensive, high-care wards for COVID-19 acute hypoxaemic respiratory failure: Comparing outcomes of the first v. third waves at a tertiary centre in South Africa.

Background: High-flow nasal oxygen (HFNO) is an accepted treatment for severe COVID-19-related acute hypoxaemic respiratory failure (AHRF). Objectives: To determine whether treatment outcomes at Groote Schuur Hospital, Cape Town, South Africa, during the third COVID-19 wave would be affected by increased institutional experience and capacity for HNFO and more restrictive admission criteria for respiratory high-care wards and intensive care units. Methods: We included consecutive patients with COVID-19-related AHRF treated with HFNO during the first and third COVID-19 waves. The primary endpoint was comparison of HFNO failure (composite of the need for intubation or death while on HFNO) between waves. Results: A total of 744 patients were included: 343 in the first COVID-19 wave and 401 in the third. Patients treated with HFNO in the first wave were older (median (interquartile range) age 53 (46 - 61) years v. 47 (40 - 56) years; p<0.001), and had higher prevalences of diabetes (46.9% v. 36.9%; p=0.006), hypertension (51.0% v. 35.2%; p<0.001), obesity (33.5% v. 26.2%; p=0.029) and HIV infection (12.5% v. 5.5%; p<0.001). The partial pressure of arterial oxygen to fraction of inspired oxygen (PaO2 /FiO2 ) ratio at HFNO initiation and the ratio of oxygen saturation/FiO2 to respiratory rate within 6 hours (ROX-6 score) after HFNO commencement were lower in the first wave compared with the third (median 57.9 (47.3 - 74.3) mmHg v. 64.3 (51.2 - 79.0) mmHg; p=0.005 and 3.19 (2.37 - 3.77) v. 3.43 (2.93 - 4.00); p<0.001, respectively). The likelihood of HFNO failure (57.1% v. 59.6%; p=0.498) and mortality (46.9% v. 52.1%; p=0.159) did not differ significantly between the first and third waves. Conclusion: Despite differences in patient characteristics, circulating viral variant and institutional experience with HFNO, treatment outcomes were very similar in the first and third COVID-19 waves. We conclude that once AHRF is established in COVID-19 pneumonia, the comorbidity profile and HFNO provider experience do not appear to affect outcome. Study synopsis: What the study adds. This study adds to the body of evidence demonstrating the utility of high-flow nasal oxygen (HFNO) in avoiding invasive mechanical ventilation (IMV) in patients with severe COVID-19 hypoxaemic respiratory failure, and shows that this utility remained consistent across different waves of the COVID-19 pandemic.Implications of the study. In resource-constrained settings, HFNO is a feasible non-invasive alternative to IMV and can be employed with favourable and consistent outcomes outside traditional critical care wards. It also confirms that the degree of gas exchange abnormality, and not pre-existing patient-related factors, circulating wave variant or provider experience, is the main predictor of HFNO failure.

Multi-layered regulation of courtship behaviour.

The fruitless gene governs courtship in male, but not female, Drosophila, yet it is expressed and specifically spliced in the brains of both sexes. New experiments reveal that a splice-recognition site retained in the mature message in females provides the basis for sex-specific translational repression.

Post-transcriptional regulation of the meiotic Cdc25 protein Twine by the Dazl orthologue Boule.

Boule, a Drosophila orthologue of the vertebrate Dazl fertility factors, is a testis-specific regulator of meiotic entry and germline differentiation. Mutations inactivating either Boule, which is an RNA-binding protein, or Twine, which is a Cdc25-type phosphatase, block meiotic entry in males. Here we show that twine and boule interact genetically. We also find that protein expression from twine messenger RNA correlates with cytoplasmic accumulation of Boule and is markedly reduced by boule mutations. Remarkably, heterologous expression of Twine rescues the boule meiotic-entry defect, indicating that the essential function of Boule at the transition from G2 to M phase during meiosis is in the control of Twine translation.

Evaluating newly approved drugs for multidrug-resistant tuberculosis (endTB): study protocol for an adaptive, multi-country randomized controlled trial.

BACKGROUND: Treatment of multidrug- and rifampin-resistant tuberculosis (MDR/RR-TB) is expensive, labour-intensive, and associated with substantial adverse events and poor outcomes. While most MDR/RR-TB patients do not receive treatment, many who do are treated for 18 months or more. A shorter all-oral regimen is currently recommended for only a sub-set of MDR/RR-TB. Its use is only conditionally recommended because of very low-quality evidence underpinning the recommendation. Novel combinations of newer and repurposed drugs bring hope in the fight against MDR/RR-TB, but their use has not been optimized in all-oral, shorter regimens. This has greatly limited their impact on the burden of disease. There is, therefore, dire need for high-quality evidence on the performance of new, shortened, injectable-sparing regimens for MDR-TB which can be adapted to individual patients and different settings. METHODS: endTB is a phase III, pragmatic, multi-country, adaptive, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of shorter treatment regimens containing new drugs for patients with fluoroquinolone-susceptible, rifampin-resistant tuberculosis. Study participants are randomized to either the control arm, based on the current standard of care for MDR/RR-TB, or to one of five 39-week multi-drug regimens containing newly approved and repurposed drugs. Study participation in all arms lasts at least 73 and up to 104 weeks post-randomization. Randomization is response-adapted using interim Bayesian analysis of efficacy endpoints. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 750 patients across 6 arms affords at least 80% power to detect the non-inferiority of at least 1 (and up to 3) experimental regimens, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per protocol populations. DISCUSSION: The lack of a safe and effective regimen that can be used in all patients is a major obstacle to delivering appropriate treatment to all patients with active MDR/RR-TB. Identifying multiple shorter, safe, and effective regimens has the potential to greatly reduce the burden of this deadly disease worldwide. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02754765. Registered on 28 April 2016; the record was last updated for study protocol version 3.3, on 27 August 2019.

Formation of slow-reacting substance of anaphylaxis in human lung tissue and cells before release.

The capacity to extract slow-reacting substance of anaphylaxis (SRS-A) from human lung tissue or cells after immunologic activation, together with the measurement of SRS-A in both the extract and the surrounding fluid, permits study of total SRS-A generation. That the material extracted is SRS-A was established by both differential bioassay and purification. SRS-A accumulation was entirely intracellular after limited IgE-dependent direct or reversed anaphylactic activation. Intracellular accumulation also generally preceded release, with generation of SRS-A continuing well beyond a plateau in the cellular SRS-A level and the release of preformed mediators. The quantity of SRS-A generated after immunologic activation was modulated by the introduction of exogenous cyclic nucleotides, revealing a site of cyclic nucleotide action distinct from that on mediator release. The capacity to determine not only the release of preformed mediators but also the generation of a newly formed mediator, the sum of SRS-A in cells and supernate, adds an additional dimension to the analysis of the cellular events of immediate hypersensitivity.

Implementing rules to improve the quality of concept post-coordination with SNOMED CT.

The use of SNOMED CT as a standard reference terminology enables interoperability between clinical systems. This reference tool provides a method for creating post-coordinated terms by users according to local needs. While the creation of these terms is free, there are a number of rules, as defined in the user manual of SNOMED CT that must be followed.The Hospital Italiano of Buenos Aires has a Terminology Server that encodes medical terms, using SNOMED CT as the reference vocabulary. An interoperability analysis performed with the Nebraska Medical Center in 2006 found a high error rate (26%) in post-coordinated terms. Therefore, we implemented an automatic system of rules within the Terminology Server as defined in the user manual. Following rules implementation, the error rate decreased from 26% to 2%.

Clinical perspectives on treatment of rifampicin-resistant/multidrug-resistant TB.

Rapid diagnostics, newer drugs, repurposed medications, and shorter regimens have radically altered the landscape for treating rifampicin-resistant TB (RR-TB) and multidrug-resistant TB (MDR-TB). There are multiple ongoing clinical trials aiming to build a robust evidence base to guide RR/MDR-TB treatment, and both observational studies and programmatic data have contributed to advancing the treatment field. In December 2019, the WHO issued their second 'Rapid Communication´ related to RR-TB management. This reiterated their prior recommendation that a majority of people with RR/MDR-TB receive all-oral treatment regimens, and now allow for specific shorter duration regimens to be used programmatically as well. Many TB programs need clinical advice as they seek to roll out such regimens in their specific setting. In this Perspective, we highlight our early experiences and lessons learned from working with National TB Programs, adult and pediatric clinicians and civil society, in optimizing treatment of RR/MDR-TB, using shorter, highly-effective, oral regimens for the majority of people with RR/MDR-TB.

The mechanics of setting up a COVID-19 response: Experiences of the COVID-19 epidemic from Groote Schuur Hospital, Cape Town, South Africa.

The SARS-CoV-2 pandemic has challenged the provision of healthcare in ways that are unprecedented in our lifetime. Planning for the sheer numbers expected during the surge has required public hospitals to de-escalate all non-essential clinical services to focus on COVID-19. Western Cape Province was the initial epicentre of the COVID-19 epidemic in South Africa (SA), and the Cape Town metro was its hardest-hit geographical region. We describe how we constructed our COVID-19 hospital-wide clinical service at Groote Schuur Hospital, the University of Cape Town's tertiary-level teaching hospital. By describing the barriers and enablers, we hope to provide guidance rather than a blueprint for hospitals elsewhere in SA and in low-resource countries that face similar challenges now or during subsequent waves.

Clinical management of COVID-19: Experiences of the COVID-19 epidemic from Groote Schuur Hospital, Cape Town, South Africa.

The SARS-CoV-2 pandemic has presented clinicians with an enormous challenge in managing a respiratory virus that is not only capable of causing severe pneumonia and acute respiratory distress syndrome, but also multisystem disease. The extraordinary pace of clinical research, and particularly the surge in adaptive trials of new and repurposed treatments, have provided rapid answers to questions of whether such treatments work, and has resulted in corticosteroids taking centre stage in the management of hospitalised patients requiring oxygen support. Some treatment modalities, such as the role of anticoagulation to prevent and treat potential thromboembolic complications, remain controversial, as does the use of high-level oxygen support, outside of an intensive care unit setting. In this paper, we describe the clinical management of COVID-19 patients admitted to Groote Schuur Hospital, a major tertiary level hospital at the epicentre of South Africa's SARS-CoV-2 epidemic during its first 4 months.

FH proteins as cytoskeletal organizers.

Regulation of cell shape is a poorly understood yet central issue in cell biology. Recent experiments indicate that FH proteins link cellular signalling pathways to changes in cell shape. Members of the FH protein family play essential roles in cytokinesis and in driving alterations in cell polarity. This review discusses the structure and function of these proteins and examines the evidence that they interact specifically with Rho GTPases and profilin to organize the actin-based cytoskeleton.

Microtubule assembly in cultivated Greene melanoma cells is stimulated by dibutyryl adenosine 3':5'-cyclic monophosphate or cholera toxin.

Both dibutyryl cyclic AMP (DBcAMP) and cholera toxin promote the formation and elongation of processes of cultivated Greene hamster melanoma cells. The formation and maintenance of these processes, which contain many microtubules, are sensitive to colcemid and vinblastine. Tubulin was measured by [3H]colchicine binding and by acrylamide gel electrophoresis. We found that DBcAMP or cholera toxin increases the ratio of polymerized to unpolymerized tubulin but not the total amount of tubulin per cell. The sum of the lengths of microtubules per unit area was significantly greater in cells treated with DBcAMP than in control cells. Our findings support the hypothesis that cyclic AMP promotes the elongation of cell processes by stimulating the assembly of microtubules from existing tubulin.

Biochemical topology: applications to DNA recombination and replication.

Processes of DNA rearrangement such as recombination or replication frequently have as products different subsets of the limitless number of distinguishable catenanes or knots. The use of gel electrophoresis and electron microscopy for analysis of these topological isomers has made it possible to deduce physical and geometric features of DNA structure and reaction mechanisms that are otherwise experimentally inaccessible. Quantitative as well as qualitative characterization is possible for any pathway in which the fate of a circular DNA can be followed. The history, theory, and techniques are reviewed and illustrative examples from recent studies are presented.

Resource concentration and herbivory in oak forests.

Larvae of the fall cankerworm (Alsophila pometaria), a polyphagous defoliator of canopy trees, hatch at the time of budbreak of scarlet oak (Quercus coccinea), about 10 days before budbreak of white oak (Quercus alba). Thus the Alsophila population was dense in a site dominated by scarlet oaks and defoliated the scattered white oaks when they came into leaf. In a site dominated by white oaks, the Alsophila population was sparse and chiefly attacked scattered scarlet oak. Thus in each stand, the rarer species of tree suffered greater herbivory, in-contrast to the more commonly reported observation that herbivore attack on a plant species increases with density.

Discovery of a predicted DNA knot substantiates a model for site-specific recombination.

The mechanism of site-specific genetic recombination mediated by Tn3 resolvase has been investigated by a topological approach. Extrapolation of a detailed model of synapsis and strand exchange predicts the formation of an additional DNA product with a specific knotted structure. Two-dimensional gel electrophoresis of DNA reacted in vitro revealed a product, about 0.1 percent of the total, with the appropriate mobility. A technique for determining DNA topology by electron microscopy was improved such that less than a nanogram of DNA was required. The structure of the knot was as predicted, providing strong evidence for the model and showing the power of the topological method.

Predicting worsening asthma control following the common cold.

The asthmatic response to the common cold is highly variable, and early characteristics that predict worsening of asthma control following a cold have not been identified. In this prospective multicentric cohort study of 413 adult subjects with asthma, the mini-Asthma Control Questionnaire (mini-ACQ) was used to quantify changes in asthma control and the Wisconsin Upper Respiratory Symptom Survey-21 (WURSS-21) to measure cold severity. Univariate and multivariable models were used to examine demographic, physiological, serological and cold-related characteristics for their relationship to changes in asthma control following a cold. Clinically significant worsening of asthma control was observed following a cold (mean+/-SD increase in mini-ACQ score of 0.69+/-0.93). Univariate analysis demonstrated that season, centre location, cold duration and cold severity measurements were all associated with a change in asthma control. Multivariable analysis of the covariates available within the first 2 days of cold onset revealed that the day 2 and cumulative sum of day 1 and 2 WURSS-21 scores were significant predictors of the subsequent changes in asthma control. In asthmatic subjects, cold severity within the first 2 days can be used to predict subsequent changes in asthma control. This information may help clinicians prevent deterioration in asthma control following a cold.

Toll signaling: the enigma variations.

Experiments reported in the past year have revealed considerable diversity in Toll-mediated pathways for signal transduction in development and innate immunity. Rather than function as a well conserved signaling cassette, Toll receptors and associated factors have apparently evolved as a diverse set of configurations to defend against microbial infection in species ranging from plants to humans.

Ordering gene function: the interpretation of epistasis in regulatory hierarchies.

The order of action of genes in a regulatory hierarchy that is governed by a signal can often be determined by the method of epistasis analysis, in which the phenotype of a double mutant is compared with that of single mutants. The epistatic mutation may be in either the upstream or the downstream gene, depending on the nature of the two mutations and the type of regulation. Nevertheless, when the regulatory hierarchy satisfies certain conditions, simple rules allow the position of the epistatic locus in the pathway to be determined without detailed knowledge of the nature of the mutations, the pathway, or the molecular mechanism of regulation.

Arylsulfatase B of human lung. Isolation, characterization, and interaction with slow-reacting substance of anaphylaxis.

Arylsulfatase B was separated from arylsulfatase A in extracts of human lung tissue by anion exchange chromatography and further purified by gel filtration and cation exchange chromatography. Arylsulfatase B of human lung was similar to that enzyme in other tissues and species, exhibiting an apparent mol wt of approximately 60,000, a pH optimum for cleavage of 4-nitrocatechol sulfate (pNCS) of 5.5-6.0, and a sensitivity to inhibition by phosphate ions and especially pyrophosphate in the presence of NaCl. Human lung arylsulfatase B inactivated slow-reacting substance of anaphylaxix (SRS-A) in a linear time-dependent reaction in which the rate was determined by the enzyme-to-substrate ratio. Cleavage of pNCS by human lung arylsulfatase B was competitively suppressed by SRS-A. The finding that human lung tissue contains predominately arylsulfatase B discloses a potential regulatory mechanism for inactivation of SRS-A at or near the site of its generation.

Enhancement of random migration and chemotactic response of human leukocytes by ascorbic acid.

Incubation of human leukocytes with ascorbic acid at neutral pH and at concentrations 10-50 times that of normal blood levels augmented both the in vitro random migration and chemotaxis of the cells by 100-300% without influencing their phagocytic capacity. Enhancement of mobility by ascorbate was evident for isolated neutrophils, eosinophils, and mono-nuclear leukocytes and was independent of the specific chemotactic stimulus. Stimulation by ascorbate of the hexose monophosphate shunt of adherent neutrophils and augmentation by ascorbate of neutrophil mobility had comparable dose-response relationships, could be reversed by washing the cells, and were both suppressed by preincubation of the neutrophils with 6-aminonicotinamide, but not with the neutrophil-immobilizing factor. Glutathione, the proposed intermediate for ascorbate action, similarly stimulated hexose monophosphate shunt activity and enhanced migration. The enhancement in vitro of leukocyte mobility by ascorbate at concentrations found in some normal tissues, therefore, appears to be dependent upon stimulation of the leukocyte hexose monophosphate shunt.