The evolutionary conserved TLDc domain defines a new class of (H+)V-ATPase interacting proteins

We recently found that nuclear receptor coactivator 7 (Ncoa7) and Oxr1 interact with the proton-pumping V-ATPase. Ncoa7 and Oxr1 belong to a group of proteins playing a role in the oxidative stress response, that contain the conserved “TLDc” domain. Here we asked if the three other proteins in this family, i.e., Tbc1d24, Tldc1 and Tldc2 also interact with the V-ATPase and if the TLDc domains are involved in all these interactions. By co-immunoprecipitation, endogenous kidney Tbc1d24 (and Ncoa7 and Oxr1) and overexpressed Tldc1 and Tldc2, all interacted with the V-ATPase. In addition, purified TLDc domains of Ncoa7, Oxr1 and Tldc2 (but not Tbc1d24 or Tldc1) interacted with V-ATPase in GST pull-downs. At the amino acid level, point mutations G815A, G845A and G896A in conserved regions of the Ncoa7 TLDc domain abolished interaction with the V-ATPase, and S817A, L926A and E938A mutations resulted in decreased interaction. Furthermore, poly-E motifs upstream of the TLDc domain in Ncoa7 and Tldc2 show a (nonsignificant) trend towards enhancing the interaction with V-ATPase. Our principal finding is that all five members of the TLDc family of proteins interact with the V-ATPase. We conclude that the TLDc motif defines a new class of V-ATPase interacting regulatory proteins.

Harsh but Expedient: Dominant Leaders Increase Group Cooperation via Threat of Punishment

Dominant leadership is, surprisingly, on the rise globally. Previous studies have found that intergroup conflict increases followers’ support for dominant leaders, but identifying the potential benefits that such leaders can supply is crucial to explaining their rise. We took a behavioral-economics approach in Study 1 ( N = 288 adults), finding that cooperation among followers increases under leaders with a dominant reputation. This pattern held regardless of whether dominant leaders were assigned to groups, elected through a bidding process, or leading under intergroup competition. Moreover, Studies 2a to 2e ( N = 1,022 adults) show that impressions of leader dominance evoked by personality profiles, authoritarian attitudes, or physical formidability similarly increase follower cooperation. We found a weaker but nonsignificant trend when dominance was cued by facial masculinity and no evidence when dominance was cued by aggressive disposition in a decision game. These findings highlight the unexpected benefits that dominant leaders can bestow on group cooperation through threat of punishment.

Survival in Patients With Suspected Myocardial Infarction With Nonobstructive Coronary Arteries: A Comprehensive Systematic Review and Meta-Analysis From the MINOCA Global Collaboration

Background: Suspected myocardial infarction (MI) with nonobstructive coronary arteries (MINOCA) occurs in ≈5% to 10% of patients with MI referred for coronary angiography. The prognosis of these patients may differ to those with MI and obstructive coronary artery disease (MI-CAD) and those without a MI (patients without known history of MI [No-MI]). The primary objective of this study is to evaluate the 12-month all-cause mortality of patients with MINOCA. Methods: Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, the terms “MI,” “nonobstructive,” “angiography,” and “prognosis” were searched in PubMed and Embase databases from inception to December 2018, including original, English language MINOCA studies with >100 consecutive patients. Publications with a heterogeneous cohort, unreported coronary stenosis, or exclusively focusing on MINOCA-mimicking conditions, were excluded. Unpublished data were obtained from the MINOCA Global Collaboration. Data were pooled and analyzed using Paule-Mandel, Hartung, Knapp, Sidik & Jonkman, or restricted maximum-likelihood random-effects meta-analysis methodology. Heterogeneity was assessed using Cochran’s Q and I 2 statistics. The primary outcome was 12-month all-cause mortality in patients with MINOCA, with secondary comparisons to MI-CAD and No-MI. Results: The 23 eligible studies yielded 55 369 suspected MINOCA, 485 382 MI-CAD, and 33 074 No-MI. Pooled meta-analysis of 14 MINOCA studies accounting for 30 733 patients revealed an unadjusted 12-month all-cause mortality rate of 3.4% (95% CI, 2.6%–4.2%) and reinfarction (n=27 605; 10 studies) in 2.6% (95% CI, 1.7%–3.5%). MINOCA had a lower 12-month all-cause mortality than those with MI-CAD (3.3% [95% CI, 2.5%–4.1%] versus 5.6% [95% CI, 4.1%–7.0%]; odds ratio, 0.60 [95% CI, 0.52–0.70], P <0.001). In contrast, there was a statistically nonsignificant trend towards increased 12-month all-cause mortality in patients with MINOCA (2.6% [95% CI, 0%–5.9%]) compared with No-MI (0.7% [95% CI, 0.1%–1.3%]; odds ratio, 3.71 [95% CI, 0.58–23.61], P =0.09). Conclusions: In the largest contemporary MINOCA meta-analysis to date, patients with suspected MINOCA had a favorable prognosis compared with MI-CAD, but statistically nonsignificant trend toward worse outcomes compared to those with No-MI. Registration: URL: https://www.crd.york.ac.uk/PROSPERO/ ; Unique identifier: CRD42020145356.

The Evolutionary Conserved TLDc Domain Defines a New Class of (H+)V-ATPase Interacting Proteins

We recently found that nuclear receptor coactivator 7 (Ncoa7) and Oxr1 interact with the proton-pumping V-ATPase. Ncoa7 and Oxr1 belong to a group of proteins playing a role in the oxidative stress response, that contain the conserved “TLDc” domain. Here we asked if the three other proteins in this family, i.e., Tbc1d24, Tldc1 and Tldc2 also interact with the V-ATPase and if the TLDc domains are involved in all these interactions. By co-immunoprecipitation, endogenous kidney Tbc1d24 (and Ncoa7 and Oxr1) and overexpressed Tldc1 and Tldc2, all interacted with the V-ATPase. In addition, the purified TLDc domains of Ncoa7, Oxr1 and Tldc2 (but not Tbc1d24 or Tldc1) interacted with V-ATPase in GST pull-downs. At the amino acid level, the point mutations G815A, G845A and G896A in conserved regions of the Ncoa7 TLDc domain abolished interaction with the V-ATPase, and S817A, L926A and E938A mutations resulted in decreased interaction. Furthermore, poly-E motifs present upstream of the TLDc domain in Ncoa7 and Tldc2 enhancedshow a (nonsignificant) trend towards enhancing the interaction with V-ATPase. Our principal finding is that all five members of the TLDc family of proteins interact with the V-ATPase. We conclude that the TLDc motif defines a new class of V-ATPase interacting regulatory proteins.

Dorsal Root Ganglion Morphometric Changes Under Oxaliplatin Treatment

Purpose Magnetic resonance neurography (MRN) can detect dorsal root ganglia (DRG) hypertrophy in patients with oxaliplatin-induced peripheral neuropathy (OXIPN) but is difficult to apply in clinical daily practice. Aims of this study were (i) to assess whether DRG volume is reliably measurable by routine computed tomography (CT) scans, (ii) to measure longitudinal changes in DRG during and after oxaliplatin administration and (iii) to assess correlation between DRG morphometry and individual oxaliplatin dose. Methods For comparison of MRN and CT measurements, CT scans of 18 patients from a previous MRN study were analyzed. For longitudinal assessment of DRG size under treatment, 96 patients treated with oxaliplatin between January and December 2014 were enrolled retrospectively. DRG volumetry was performed by analyzing routine CT scans, starting with the last scan before oxaliplatin exposure (t0) and up to four consecutive timepoints after initiation of oxaliplatin therapy (t1–t4) with the following median and ranges in months: 3.1 (0.4–4.9), 6.2 (5.3–7.8), 10.4 (8.2–11.9), and 18.4 (12.8–49.8). Results DRG volume measured in CT showed a moderately strong correlation with MRN (r = 0.51, p < 0.001) and a strong correlation between two consecutive CTs (r = 0.77, p < 0.001). DRG volume increased after oxaliplatin administration with a maximum at timepoint t2. Higher cumulative oxaliplatin exposure was associated with significantly higher absolute DRG volumes (p = 0.005). Treatment discontinuation was associated with a nonsignificant trend towards lower relative DRG volume changes (p = 0.08). Conclusion CT is a reliable method for continuous DRG morphometry; however, since no standardized assessment of OXIPN was performed in this retrospective study, correlations between DRG size, cumulative oxaliplatin dose and clinical symptoms in future prospective studies are needed to establish DRG size as a potential OXIPN biomarker.

The Pen Is Milder Than the Blade: Identification Marking Mice Using Ink on the Tail Appears More Humane Than Ear-Punching Even with Local Anaesthetic

Identification marking mice commonly involves ear-punching with or without anaesthetic, or tail-marking with ink. To identify which is most humane, we marked weanling male BALB/c mice using ear-punching (EP), ear-punching with anaesthetic EMLATM cream (EP+A), or permanent marker pen (MP). We compared marked mice, unmarked cagemates, and control mice (n = 12–13/group) for 5 weeks, reapplying MP weekly. Treatment-blind observations following marking showed that EP and EP+A mice were allogroomed (p < 0.001) and sniffed (p < 0.001) by their cagemates more than MP and control mice were. EP+A mice groomed themselves (p < 0.001) and their ears (p < 0.001) ~5 times more than most other mice; their cagemates also increased self-grooming (p < 0.001). Unmarked MP cagemates (p = 0.001), and possibly EP+A mice (p = 0.034; a nonsignificant trend), grimaced the most. The following day, half the EP+A mice showed hyponeophagia versus no MP and control mice (p = 0.001). Over the 5 weeks, EP mice approached the handler significantly less than unmarked cagemates did (p < 0.001). Across weeks, defecation during marking of MP mice decreased (p < 0.001). Treatment showed no effects on immediate responses during marking, aggression, bodyweight, plus-maze behaviour or corticosterone. MP mice showed no differences from controls, whilst EP and EP+A mice showed altered behaviour, so ink-marking may be the more humane identification method.

Prosthetic Shoulder Joint Infection by Cutibacterium acnes: Does Rifampin Improve Prognosis? A Retrospective, Multicenter, Observational Study

This retrospective, multicenter observational study aimed to describe the outcomes of surgical and medical treatment of C. acnes-related prosthetic joint infection (PJI) and the potential benefit of rifampin-based therapies. Patients with C. acnes-related PJI who were diagnosed and treated between January 2003 and December 2016 were included. We analyzed 44 patients with C. acnes-related PJI (median age, 67.5 years (IQR, 57.3–75.8)); 75% were men. The majority (61.4%) had late chronic infection according to the Tsukayama classification. All patients received surgical treatment, and most antibiotic regimens (43.2%) included β-lactam. Thirty-four patients (87.17%) were cured; five showed relapse. The final outcome (cure vs. relapse) showed a nonsignificant trend toward higher failure frequency among patients with previous prosthesis (OR: 6.89; 95% CI: 0.80–58.90) or prior surgery and infection (OR: 10.67; 95% IC: 1.08–105.28) in the same joint. Patients treated with clindamycin alone had a higher recurrence rate (40.0% vs. 8.8%). Rifampin treatment did not decrease recurrence in patients treated with β-lactams. Prior prosthesis, surgery, or infection in the same joint might be related to recurrence, and rifampin-based combinations do not seem to improve prognosis. Debridement and implant retention appear a safe option for surgical treatment of early PJI.

Ngaa-bi-nya-nhumi-nya (to Test First): Piloting the Feasibility of Using the Growth and Empowerment Measure with Aboriginal Pregnant Women Who Smoke

Introduction. Aboriginal pregnant women who smoke experience barriers to quitting, including challenges to social and emotional well-being, but these are infrequently quantified. Finding an appropriate measurement tool in this setting is crucial to increase knowledge for holistic smoking cessation interventions. Aims. To pilot the Growth and Empowerment Measure (GEM) with a sample of pregnant Aboriginal women who smoke. Methods. Aboriginal women participating in the step-wedge ICAN QUIT in Pregnancy pilot study completed the GEM comprised of 14-item Emotional Empowerment Scale (EES14), 12 Scenarios (12S), and K6 items at baseline, 4 weeks, and 12 weeks. Qualitative interviews with service staff were held at the end of the study to assess feasibility. Results. 15 pregnant Aboriginal women took part between November 2016 and July 2017. At 12 weeks, n = 8 / 12 (67%) of women reported an increase in both the EES14 and 12S scores. Total 12S scores were significantly higher at 12 weeks ( p = 0.0186 ). Total K6 had a nonsignificant trend for reduction ( p = 0.0547 ). Staff reported that the length of the survey presents challenges in this setting. Conclusions. A shortened, modified GEM is recommended in this setting. We recommend the GEM to be tested in a larger study, powered to assess its associations with smoking behaviours.

Merging Two Hospitals: The Effects on Pediatric Extracorporeal Cardiopulmonary Resuscitation Outcomes

A retrospective study was performed to describe the impact of merging two pediatric intensive care units on the overall and neurocognitive outcomes of children who required extracorporeal cardiopulmonary resuscitation (ECPR). Results from three cohorts were compared: 2008 to 2014: premerge, 2014 to 2017: initial time period postmerge, and 2018 to 2019: established merge. Survival to hospital discharge (and with good neurological outcome) was of 68% (61%), 46% (36%), and 79% (71%), respectively, for the three time periods. Merging two hospitals resulted in a nonsignificant trend toward temporary worse outcomes in pediatric patients requiring ECPR.

Does Item Difficulty Affect the Magnitude of the Retrieval Practice Effect? An Evaluation of the Retrieval Effort Hypothesis

Retrieving information by testing improves subsequent retention more than restudy, a phenomenon known as the retrieval practice effect. According to the retrieval effort hypothesis (REH), difficult items require more retrieval effort than easier items and, consequently, should benefit more from retrieval practice. In two experiments, we tested this prediction. Participants learned sets of easy and difficult Swahili–Portuguese word pairs (study phase) and repeatedly restudied half of these items and repeatedly retrieval practiced the other half (practice phase). Forty-eight hours later, they took a cued-recall test (final test phase). In both experiments, we replicated both the retrieval practice and the item difficulty effects. In Experiment 1 (N = 51), we found a greater retrieval practice effect for easy items, MDifference = .26, SD = .17, than for difficult items, MDifference = .19, SD = .19, t(50) = 2.01, p = .05, d = 0.28. In Experiment 2 (N = 28), we found a nonsignificant trend—F(1, 27) = 2.86, p = .10, $$ {\upeta}_{\mathrm{p}}^2 $$ = .10—toward a greater retrieval practice effect for difficult items, MDifference = .28, SD = .22, than for easy items, MDifference = .18, SD = .21. This was especially true for individuals who benefit from retrieval practice (difficult: MDifference = .32, SD = .18; easy: MDifference = .20, SD = .20), t(24) = –2.08, p = .05, d = –0.42. The results provide no clear evidence for the REH and are discussed in relation to current accounts of the retrieval practice effect.