Virtual discussion groups: a proposal for nursing teaching

This paper describes a teaching experience aimed at providing interactivity to the technique of field diary by using a virtual learning environment. The educational proposal derives from the Federal University of Rio Grande do Sul (UFRGS)'s Teaching Training Program of the Stricto Sensu Post-Graduation Program in Nursing, in which the author, a Master's degree candidate, oriented by her advisor, proposed forming virtual discussion groups in order to write the field diary for an undergraduate discipline in Nursing, with the aim of providing an opportunity for a joint discussion of academic experiences in the realm of practice. The instructors of the discipline in which the proposal was developed also participated in the activities. The virtual technology gave new dynamism to the technique of field diary, making possible an exchange of experiences among the students, the instructor and the author, as well as moments of reflection and discussion regarding the themes faced in the Nursing practice.     

Endocrine Dysfunction in Children with Zika-Related Microcephaly Who Were Born during the 2015 Epidemic in the State of Pernambuco,Brazil

Congenital viral infections and the occurrence of septo-optic dysplasia, which is a combination of optic nerve hypoplasia, abnormal formation of structures along the midline of the brain, and pituitary hypofunction, support the biological plausibility of endocrine dysfunction in Zika-related microcephaly. In this case series we ascertained the presence and describe endocrine dysfunction in 30 children with severe Zika-related microcephaly from the MERG Pediatric Cohort, referred for endocrinological evaluation between February and August 2019. Of the 30 children, 97% had severe microcephaly. The average age at the endocrinological consultation was 41 months and 53% were female. The most frequently observed endocrine dysfunctions comprised short stature, hypothyroidism, obesity and variants early puberty. These dysfunctions occurred alone 57% or in combination 43%. We found optic nerve hypoplasia (6/21) and corpus callosum hypoplasia (20/21). Seizure crises were reported in 86% of the children. The most common—and clinically important—endocrine dysfunctions were pubertal dysfunctions, thyroid disease, growth impairment, and obesity. These dysfunctions require careful monitoring and signal the need for endocrinological evaluation in children with Zika-related microcephaly, in order to make early diagnoses and implement appropriate treatment when necessary.     

Longevity of the novel ConvaTec infusion set with Lantern technology

Current insulin infusion sets are approved for only 2-3 days. The novel ConvaTec infusion set with Lantern technology is designed to extend infusion set wear time. The goal of this pilot study was to evaluate the duration of wear for this set. This was a pilot safety study in adults with type 1 diabetes using tethered insulin pumps. Participants inserted the set and wore it for 10 days or until failure. Among 24 participants, two were excluded. Forty-five per cent of the sets lasted 10 days. Median wear time was 9.1 (7.1, 10.0) days. Among 12 premature failures, six (50%) involved adhesive failures, four (33%) hyperglycaemia unresponsive to correction, one (8%) hyperglycaemia with ketones and one (8%) infection. Average CGM glucose per day of infusion set wear showed a statistically significant increase over time, while total daily insulin over the same period did not change. In this pilot study, the duration of wear for the novel infusion set exceeded previously reported commercial sets (P < .001). This extended wear technology may eventually allow for a combined glucose sensor and infusion set.     

From the Cover: PACAP is a pathogen-inducible resident antimicrobial neuropeptide affording rapid and contextual molecular host defense of the brain

Defense of the central nervous system (CNS) against infection must be accomplished without generation of potentially injurious immune cell-mediated or off-target inflammation which could impair key functions. As the CNS is an immune-privileged compartment, inducible innate defense mechanisms endogenous to the CNS likely play an essential role in this regard. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide known to regulate neurodevelopment, emotion, and certain stress responses. While PACAP is known to interact with the immune system, its significance in direct defense of brain or other tissues is not established. Here, we show that our machine-learning classifier can screen for immune activity in neuropeptides, and correctly identified PACAP as an antimicrobial neuropeptide in agreement with previous experimental work. Furthermore, synchrotron X-ray scattering, antimicrobial assays, and mechanistic fingerprinting provided precise insights into how PACAP exerts antimicrobial activities vs. pathogens via multiple and synergistic mechanisms, including dysregulation of membrane integrity and energetics and activation of cell death pathways. Importantly, resident PACAP is selectively induced up to 50-fold in the brain in mouse models of Staphylococcus aureus or Candida albicans infection in vivo, without inducing immune cell infiltration. We show differential PACAP induction even in various tissues outside the CNS, and how these observed patterns of induction are consistent with the antimicrobial efficacy of PACAP measured in conditions simulating specific physiologic contexts of those tissues. Phylogenetic analysis of PACAP revealed close conservation of predicted antimicrobial properties spanning primitive invertebrates to modern mammals. Together, these findings substantiate our hypothesis that PACAP is an ancient neuro-endocrine-immune effector that defends the CNS against infection while minimizing potentially injurious neuroinflammation.

Neuropeptides enable interneuronal communication and signaling (1), mediating diverse functions ranging from endocrine stimulation and homeostatic regulation to immune signaling, pain modulation, and circadian rhythm maintenance. At present, over 100 neuropeptides are known in mammals (2). These peptides originate from neurons in the central, enteric, or peripheral nervous systems and within immune organs (3). Canonically, neuropeptides exert their biological function by binding to a cognate receptor (usually a G-coupled protein receptor [GPCR]), triggering a signal transduction pathway that leads to a functional change in the target cell (1). Neuropeptides are typically considered neurotransmitters or neurohormones, but recent work has illuminated their potential roles in modulating immune responses and neuroinflammation (4–8).Human innate and adaptive immunity have evolved via two parallel and complementary paradigms in host defense against microbial invasion: molecular and cellular. Molecular defense mediators are secreted or activated rapidly and locally to directly inhibit pathogens. Prototypic examples include host-defense peptides (HDPs), the acute-phase reactants, and the complement cascade. Cellular defense involves infiltration of professional immune phagocytes (neutrophils and macrophages) and lymphocytes into infected tissues. Cellular infiltration into the central nervous system (CNS) is a double-edged sword, given its anatomically confined space and physiologically delicate context. On one hand cellular defense may be necessary to control or clear certain pathogens. On the other hand, neutrophils and other phagocytes can cause counterproductive damage to tissue parenchyma due to production and release of reactive oxygen species and other cytotoxic constituents from phagolysosomes. Thus, molecular defenses that are rapidly deployable in immediate settings of infection to obviate the need for infiltration of potentially harmful immune cells would be of special relevance in context of the CNS.To explore putative molecular host-defense mediators within the CNS that may have both neuro- and immunomodulatory properties, we used a support vector machine (SVM) trained on HDPs (9, 10) to identify neuropeptides with potential host defense capabilities. Among the human neuropeptides identified as potential HDPs for molecular host defense of the CNS is pituitary adenylate cyclase-activating polypeptide (PACAP). PACAP is a member of the vasoactive intestinal peptide (VIP)/PACAP/secretin family (11) that regulates neurodevelopment (12), metabolism, emotion, mood, and stress responses via GPCRs (13). PACAP is known to interact with the immune system (14, 15) and modulate T helper type 1 (TH1)/TH2 cytokine production (3). Important previous work on structure activity relationships (SAR) of PACAP have also shown that it possess antimicrobial activity in vitro against a range of organisms (16–18), as well as anti-cancer activity against tumor cell lines. (Interestingly, our use of an SVM classifier that can scan different fragments of the same peptide allows us to identify antimicrobial activity in previously identified metabolites of PACAP as well^* (19)). However, host defense functions, contextual bioactivity, or pathogen-specific inducibility of PACAP or other neuropeptides regarding antimicrobial activity in vivo are not known. More specifically, the role of PACAP in the larger context of innate immunity and its in vivo relevance to antimicrobial defense of the CNS and in other tissues remains unclear, given that antimicrobial activity is strongly dependent on biochemical and physiological context (20, 21, 22). Here, we examine PACAP inducibility in response to infection in the CNS and other tissues, and whether PACAP exerts antimicrobial activity against relevant organisms in the specific biochemical context relevant to those tissues. Bioinformatic and structural analyses showed PACAP to possess almost identical structural similarity to human cathelicidin LL-37, despite having overall low sequence similarity to other known HDPs. Synchrotron X-ray scattering revealed that PACAP can induce negative Gaussian curvature (NGC) in microbial membranes, a general requirement for membrane-permeating antimicrobial processes such as pore formation, blebbing, and other membrane-perturbing events (23–25). Moreover, extending from prior work (18), antimicrobial assays and mechanistic fingerprinting analyses showed that PACAP exerts potent antimicrobial mechanisms against drug-resistant bacteria and fungi via multiple synergistic pathways, including permeabilization, disruption of cellular energetics, and activation of regulated cell death pathways. In mouse models of bacterial or fungal infection, we demonstrated that PACAP is strongly induced up to 50-fold in brain, spleen, or kidney. Further, in media simulating these tissue contexts, PACAP exerted robust microbiostatic and microbicidal efficacy. Taken together, these findings imply that PACAP is an infection-inducible, tissue-specific host-defense effector that affords rapid and contextual antimicrobial host defense in the CNS and periphery. Beyond immediate contributions to better understanding of antimicrobial defense, the present discoveries reveal specific intersections of neurological and immunological systems and establish insights into antiinfective strategies that preserve critical functions of the CNS.     

Benefits and Sustainability of a Learning Collaborative for Implementation of Treat‐to‐Target in Rheumatoid Arthritis: Results of a Cluster‐Randomized Controlled Phase II Clinical Trial

Objective

We conducted a 2‐phase randomized controlled trial of a learning collaborative to facilitate implementation of treat‐to‐target (T2T) to manage rheumatoid arthritis (RA). We found substantial improvement in implementation of T2T in phase I. Here, we report on a second 9 months (phase II), where we examined the maintenance of response in phase I and predictors of greater improvement in T2T adherence.

Methods

We recruited patients from 11 rheumatology sites and randomized them to either receive the learning collaborative during phase I or to a wait‐list control group that received the learning collaborative intervention during phase II. The outcome was change in T2T implementation score (0–100, where 100 = best) from pre‐ to postintervention. The T2T implementation score was defined as a percent of components documented in visit notes. Analyses examined the extent to which the phase‐I intervention teams sustained improvement in T2T, as well as predictors of T2T improvement.

Results

The analysis included 636 RA patients. At baseline, the mean T2T implementation score was 11% in phase I intervention sites and 13% in phase II sites. After the intervention, T2T implementation score improved to 57% in the phase I intervention sites and to 58% in the phase II sites. Intervention sites from phase I sustained the improvement during the phase II (52%). Predictors of greater T2T improvement included having only rheumatologist providers at the site, academic affiliation of the site, having fewer providers per site, and the rheumatologist provider being a trainee.

Conclusion

Improvement in T2T remained relatively stable over a postintervention period.

     

Long-term safety and efficacy of the PI3K inhibitor copanlisib in patients with relapsed or refractory indolent lymphoma: 2-year follow-up of the CHRONOS-1 study

Safety profiles of oral PI3K inhibitors have resulted in US FDA black box warnings regarding fatal/serious toxicities. The approved intravenous PI3K inhibitor copanlisib has low incidence of severe toxicities and no black box warnings, but chronic treatment effects were unknown. We provide an update on safety and efficacy of copanlisib with a minimum 2-year follow-up of the CHRONOS-1 study. A total of 142 patients with histologically confirmed indolent B-cell lymphoma who had relapsed after or were refractory to ≥2 prior treatments received intravenous copanlisib 60 mg on days 1, 8, and 15 (28-day cycle). The primary efficacy endpoint was objective response rate (ORR) after ≥4 cycles (independent assessment). The predominant histology was follicular lymphoma (n = 104). The ORR was 60.6% (seven additional complete responses since primary analysis). Secondary endpoints of median duration of response, progression-free survival, and overall survival were 14.1 months (median follow-up, 16.1 months), 12.5 months (median follow-up, 14.0 months), and 42.6 months (median follow-up, 31.5 months), respectively. Median safety follow-up was 6.7 months; 26% of patients received treatment for >1 year. Common treatment-emergent adverse events (TEAEs) (all grade/grade 3/grade 4) were transient hyperglycemia (50.0%/33.1%/7.0%), diarrhea (35.2%/8.5%/0%), transient hypertension (29.6%/23.9%/0%), and neutropenia (28.9%/9.2%/14.8%). Serious AEs were largely unchanged, with no new cases of pneumonitis (4.2%), diarrhea (2.8%), or grade 5 events. Note, TEAEs showed no evidence for increased incidence or worsening following longer exposure in patients treated >1 year. Long-term follow-up of patients with relapsed/refractory indolent B-cell lymphoma treated with intravenous copanlisib demonstrated durable, enhanced responses without evidence of worsening TEAEs, as reported for orally administered PI3K inhibitors.