Guest editorial : Social prescribing

Journal guest editorial article

Hit and run versus long-term activation of PARP-1 by its different domains fine-tunes nuclear processes.

Poly(ADP-ribose) polymerase 1 (PARP-1) is a multidomain multifunctional nuclear enzyme involved in the regulation of the chromatin structure and transcription. PARP-1 consists of three functional domains: the N-terminal DNA-binding domain (DBD) containing three zinc fingers, the automodification domain (A), and the C-terminal domain, which includes the protein interacting WGR domain (W) and the catalytic (Cat) subdomain responsible for the poly(ADP ribosyl)ating reaction. The mechanisms coordinating the functions of these domains and determining the positioning of PARP-1 in chromatin remain unknown. Using multiple deletional isoforms of PARP-1, lacking one or another of its three domains, as well as consisting of only one of those domains, we demonstrate that different functions of PARP-1 are coordinated by interactions among these domains and their targets. Interaction between the DBD and damaged DNA leads to a short-term binding and activation of PARP-1. This hit and run activation of PARP-1 initiates the DNA repair pathway at a specific point. The long-term chromatin loosening required to sustain transcription takes place when the C-terminal domain of PARP-1 binds to chromatin by interacting with histone H4 in the nucleosome. This long-term activation of PARP-1 results in a continuous accumulation of pADPr, which maintains chromatin in the loosened state around a certain locus so that the transcription machinery has continuous access to DNA. Cooperation between the DBD and C-terminal domain occurs in response to heat shock (HS), allowing PARP-1 to scan chromatin for specific binding sites

Stepwise dissection of Plasmodium falciparum merozoite invasion of the human erythrocyte

A critical step in establishing malaria parasite infection is the ability of the blood stage merozoite to invade erythrocytes. However, much of our understanding about the cell biology of this process has remained unchanged since seminal work, more than 30 years ago, defined the steps of entry by light and electron microscopy. These studies were, however, only possible using merozoites from simian and avian malaria parasite species, given the poor viability of merozoites from human parasites, specifically Plasmodium falciparum. In contrast, critical invasion proteins have been best described for human or mouse parasite species. Thus our understanding about the molecular and cellular coordination of the entire process of invasion is still largely unknown. Towards addressing this gap, we recently developed a method for harvesting viable P. falciparum merozoites, permitting detailed investigation of the molecular events of merozoite invasio

Balancing cognitive diversity and mutual understanding in multidisciplinary teams.

BACKGROUND: Interprofessional health care teams are increasingly utilized in health care organizations. Although there is support for their capacity to solve complex problems, there is also evidence that such teams are not always successful. In an effort to understand the capacity of interprofessional teams to innovate successfully, we investigate the role of cognitive diversity to establish whether and how knowledge differences lead to innovation. PURPOSES: The aim of this study was to construct and investigate a model of team innovation predicted by cognitive diversity. In addition to investigating the direct impact of cognitive diversity in interprofessional health care teams, we develop a model incorporating mediated and moderated effects. In this study, we explore the role of debate as a mediating factor capable of explaining the impact of cognitive diversity on innovation. We further propose that the link between cognitive diversity and innovation through debate is contingent upon trans-specialist knowledge, knowledge shared by health care professionals, spanning specialist divides and enabling mutual understanding. METHODOLOGY: The hypotheses were investigated using a cross-sectional, correlational design. Survey data received from 75 interprofessional teams employed in an acute care setting, representing a 36% response rate, were used to investigate our model. FINDINGS: Analysis supports a significant relationship between cognitive diversity and debate, which is stronger when teams rate highly for trans-specialist knowledge. Results also support a positive relationship between debate and innovation and our full moderated mediated pathway. PRACTICE IMPLICATIONS: A range of strategies are indicated by our results to increase innovation in interprofessional teams. In particular, interventions such as interprofessional education and training, which have been shown to facilitate the development of shared language and meaning, are recommended by our findings

Vδ2+ T cell response to malaria correlates with protection from infection but is attenuated with repeated exposure.

Vδ2+ γδ T cells are semi-innate T cells that expand markedly following P. falciparum (Pf) infection in naïve adults, but are lost and become dysfunctional among children repeatedly exposed to malaria. The role of these cells in mediating clinical immunity (i.e. protection against symptoms) to malaria remains unclear. We measured Vδ2+ T cell absolute counts at acute and convalescent malaria timepoints (n = 43), and Vδ2+ counts, cellular phenotype, and cytokine production following in vitro stimulation at asymptomatic visits (n = 377), among children aged 6 months to 10 years living in Uganda. Increasing age was associated with diminished in vivo expansion following malaria, and lower Vδ2 absolute counts overall, among children living in a high transmission setting. Microscopic parasitemia and expression of the immunoregulatory markers Tim-3 and CD57 were associated with diminished Vδ2+ T cell pro-inflammatory cytokine production. Higher Vδ2 pro-inflammatory cytokine production was associated with protection from subsequent Pf infection, but also with an increased odds of symptoms once infected. Vδ2+ T cells may play a role in preventing malaria infection in children living in endemic settings; progressive loss and dysfunction of these cells may represent a disease tolerance mechanism that contributes to the development of clinical immunity to malaria

Telemedicine Critical Care-Mediated Mortality Reductions in Lower-Performing Patient Diagnosis Groups: A Prospective, Before and After Study

OBJECTIVES: Studies evaluating telemedicine critical care (TCC) have shown mixed results. We prospectively evaluated the impact of TCC implementation on risk-adjusted mortality among patients stratified by pre-TCC performance. DESIGN: Prospective, observational, before and after study. SETTING: Three adult ICUs at an academic medical center. PATIENTS: A total of 2,429 patients in the pre-TCC (January to June 2016) and 12,479 patients in the post-TCC (January 2017 to June 2019) periods. INTERVENTIONS: TCC implementation which included an acuity-driven workflow targeting an identified “lower-performing” patient group, defined by ICU admission in an Acute Physiology and Chronic Health Evaluation diagnoses category with a pre-TCC standardized mortality ratio (SMR) of greater than 1.5. MEASUREMENTS AND MAIN RESULTS: The primary outcome was risk-adjusted hospital mortality. Risk-adjusted hospital length of stay (HLOS) was also studied. The SMR for the overall ICU population was 0.83 pre-TCC and 0.75 post-TCC, with risk-adjusted mortalities of 10.7% and 9.5% (p = 0.09). In the identified lower-performing patient group, which accounted for 12.6% (n = 307) of pre-TCC and 13.3% (n = 1671) of post-TCC ICU patients, SMR decreased from 1.61 (95% CI, 1.21–2.01) pre-TCC to 1.03 (95% CI, 0.91–1.15) post-TCC, and risk-adjusted mortality decreased from 26.4% to 16.9% (p \u3c 0.001). In the remaining (“higher-performing”) patient group, there was no change in pre- versus post-TCC SMR (0.70 [0.59–0.81] vs 0.69 [0.64–0.73]) or risk-adjusted mortality (8.5% vs 8.4%, p = 0.86). There were no pre- to post-TCC differences in standardized HLOS ratio or risk-adjusted HLOS in the overall cohort or either performance group. CONCLUSIONS: In well-staffed and overall higher-performing ICUs in an academic medical center, Acute Physiology and Chronic Health Evaluation granularity allowed identification of a historically lower-performing patient group that experienced a striking TCC-associated reduction in SMR and risk-adjusted mortality. This study provides additional evidence for the relationship between pre-TCC performance and post-TCC improvement

Patients' experiences of post radiotherapy skin reactions

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FCRL5 Delineates Functionally Impaired Memory B Cells Associated with Plasmodium falciparum Exposure.

Exposure to Plasmodium falciparum is associated with circulating "atypical" memory B cells (atMBCs), which appear similar to dysfunctional B cells found in HIV-infected individuals. Functional analysis of atMBCs has been limited, with one report suggesting these cells are not dysfunctional but produce protective antibodies. To better understand the function of malaria-associated atMBCs, we performed global transcriptome analysis of these cells, obtained from individuals living in an area of high malaria endemicity in Uganda. Comparison of gene expression data suggested down-modulation of B cell receptor signaling and apoptosis in atMBCs compared to classical MBCs. Additionally, in contrast to previous reports, we found upregulation of Fc receptor-like 5 (FCRL5), but not FCRL4, on atMBCs. Atypical MBCs were poor spontaneous producers of antibody ex vivo, and higher surface expression of FCRL5 defined a distinct subset of atMBCs compromised in its ability to produce antibody upon stimulation. Moreover, higher levels of P. falciparum exposure were associated with increased frequencies of FCRL5+ atMBCs. Together, our findings suggest that FCLR5+ identifies a functionally distinct, and perhaps dysfunctional, subset of MBCs in individuals exposed to P. falciparum

Nighttime is the worst time: Parental fear of hypoglycemia in young children with type 1 diabetes

BACKGROUND: Fear of hypoglycemia is common in parents of young children with type 1 diabetes (T1D), but little is known about the specific fears that parents most often experience. Hypoglycemia fear has been associated with poorer glycemic control in older children, though not yet studied in a large cohort of very young children. MATERIALS AND METHODS: Parents of 549 children <7 years (mean 5.2 ± 1.2 years [19% <3 years]) with a mean diabetes duration of 2.4 ± 1.0 years (range 1-6 years) and mean HbA1c 8.2% ± 1.1% (66 ± 12 mmol/mol) registered in the T1D Exchange completed the worry scale of the Hypoglycemia Fear Survey modified for parents (HFS-P). RESULTS: Mean parental fear of hypoglycemia worry score was 36.1 ± 23.1 (possible range 0-100), with most frequent worries related to the child having a low while asleep and the child not recognizing a low. The mean worry score was not associated with the child's age, glycemic control, or recent severe hypoglycemic event. Parental worries about lows while sleeping were significantly higher in pump users than non-users (61% vs. 45%; P < .001), and tended to be higher in CGM users than non-users (62% vs 51%; P = .02). CONCLUSIONS: The greatest worries of parents of young children with T1D were related to hypoglycemia during sleep and other times/circumstances during which it would be difficult to detect hypoglycemia. Using advanced diabetes technologies may be an effort to temper fears about hypoglycemia during sleep, though the directionality of this relationship is undetermined. Additional studies can clarify this association and leverage use of diabetes technologies to improve glycemic control

A novel BH3 ligand that selectively targets Mcl-1 reveals that apoptosis can proceed without Mcl-1 degradation

Like Bcl-2, Mcl-1 is an important survival factor for many cancers, its expression contributing to chemoresistance and disease relapse. However, unlike other prosurvival Bcl-2–like proteins, Mcl-1 stability is acutely regulated. For example, the Bcl-2 homology 3 (BH3)–only protein Noxa, which preferentially binds to Mcl-1, also targets it for proteasomal degradation. In this paper, we describe the discovery and characterization of a novel BH3-like ligand derived from Bim, BimS2A, which is highly selective for Mcl-1. Unlike Noxa, BimS2A is unable to trigger Mcl-1 degradation, yet, like Noxa, BimS2A promotes cell killing only when Bcl-xL is absent or neutralized. Furthermore, killing by endogenous Bim is not associated with Mcl-1 degradation. Thus, functional inactivation of Mcl-1 does not always require its elimination. Rather, it can be efficiently antagonized by a BH3-like ligand tightly engaging its binding groove, which is confirmed here with a structural study. Our data have important implications for the discovery of compounds that might kill cells whose survival depends on Mcl-1