Citations

Abstract NKAP and HDAC3 are critical for T cell maturation. NKAP and HDAC3 physically associate, and a point mutation in NKAP, NKAP(Y352A), abrogates this interaction. To evaluate the significance of NKAP and HDAC3 association in T cell maturation, transgenic mice were engineered for cre-mediated endogenous NKAP gene deletion coupled to induction of NKAP(Y352A) or a wild type (WT) control transgene, NKAP(WT), in double positive thymocytes or regulatory T cells (Tregs). T cell maturation was normal in mice with endogenous NKAP deletion coupled to NKAP(WT) induction. However, severe defects occurred in T cell and Treg maturation and in iNKT cell development when NKAP(Y352A) was induced, recapitulating NKAP deficiency. Conventional T cells expressing NKAP(Y352A) failed to enter the long-term T cell pool, did not produce cytokines, and remained complement susceptible, whereas Tregs expressing NKAP(Y352A) were eliminated as recent thymic emigrants leading to lethal autoimmunity. Overall, these results demonstrate the significance of NKAP–HDAC3 association in T cells.

BackgroundAn understanding of potential age‐related changes in brain stiffness and its regional variation is important for further clinical application of MR elastography.PurposeTo investigate the effect of age on global and regional brain stiffness in young and middle‐aged adults.Study TypeProspective.SubjectsFifty subjects with normal brains and aged in their 20s, 30s, 40s, 50s, or 60s (five men, five women per decade).Field Strength/Sequence3.0T MRI and elastography with a vibration frequency of 60 Hz.AssessmentStiffness was measured in nine brain regions (cerebrum, temporal lobes, sensorimotor areas, frontotemporal composite region, deep gray matter and white matter (deep GM/WM), parietal lobes, occipital lobes, frontal lobes, and cerebellum) using an atlas‐based region‐of‐interest approach. The influence of age on regional brain stiffness was evaluated.Statistical TestsMultiple linear regression analysis, followed by Dunnett's multiple comparisons test, using subjects in their 20s as controls.ResultsFollowing adjustment for sex, multiple linear regression revealed a significant negative correlation between age and stiffness of the cerebrum (P < 0.0001), temporal lobes (P < 0.0001), sensorimotor areas (P < 0.0001), frontotemporal composite region (P < 0.0001), deep GM/WM (P = 0.0028), parietal lobes (P < 0.0001), occipital lobes (P = 0.0055), and frontal lobes (P < 0.0001). Dunnett's multiple comparison test showed that the stiffness of the sensorimotor areas, frontotemporal composite region, and frontal lobes was significantly decreased in subjects in their 40s (P < 0.0367), 50s (P < 0.0001), and 60s (P < 0.0001), while that of the cerebrum, temporal lobes, and parietal lobes was significantly decreased only in subjects in their 50s (P < 0.0012) and 60s (P < 0.0031) when compared with the controls.Data ConclusionThere is an age‐related decrease in brain stiffness that varies across the different regions.Level of Evidence: 1Technical Efficacy Stage: 2J. Magn. Reson. Imaging 2020;51:727–733.

Rewarming the intact heart after a period of hypothermia is associated with reduced myocardial contractility, decreased Ca2+ sensitivity, and increased cardiac troponin-I (cTnI) phosphorylation. We hypothesized that hypothermia/rewarming (H/R) induces left ventricular (LV) contractile dysfunction due to phosphorylation of cTnI at Ser23/24. To test this hypothesis, the response of wild-type mice ( n = 7) to H/R was compared with transgenic (TG) mice expressing slow skeletal TnI (TG-ssTnI; n = 7) that lacks the Ser23/24 phosphorylation sites. Hypothermia was induced by surface cooling and maintained at 23–25°C for 3 h. Subsequently, the animals were rewarmed to 37°C. LV systolic and diastolic function was assessed using a 1.4 F pressure-volume Millar catheter introduced via the right carotid artery. At baseline conditions, there were no significant differences in LV systolic function between wild-type and TG-ssTnI mice, whereas measurements of diastolic function [isovolumic relaxation constant (τ) and end-diastolic pressure-volume relationship (EDPVR)] were significantly ( P < 0.05) reduced in TG-ssTnI animals. Immediately after rewarming, significant differences between groups were found in cardiac output (CO; wild-type 6.6 ± 0.7 vs. TG-ssTnI 8.8 ± 0.7 mL/min), stroke work (SW; wild-type 796 ± 112 vs. TG-ssTnI 1208 ± 67 mmHg/μL), and the preload recruited stroke work (PRSW; wild-type 38.3 ± 4.9 vs. TG-ssTnI 68.8 ± 8.2 mmHg). However, EDPVR and τ returned to control levels within 1 h in both groups. We conclude that H/R-induced LV systolic dysfunction results from phosphorylation of cTnI at Ser23/24. NEW & NOTEWORTHY Rewarming following a period of accidental hypothermia leads to a form of acute cardiac failure (rewarming shock), which is in part due to reduced sensitivity to Ca2+ activation of myocardial contraction. The results of the present study support the hypothesis that rewarming shock is due to phosphorylation of cardiac troponin I.

Objectives: The ability of current return to sport (RTS) criteria to identify young, active patients after ACL reconstruction (ACLR) independently, at high risk for future ipsilateral or contralateral ACL injury is limited. The purpose of this study was to determine if meeting current, standard RTS criteria collectively, or in part, would identify young athletes at risk for an ipsilateral or contralateral ACL injury after primary ACLR and RTS. The tested hypothesis was the likelihood of an ipsilateral or contralateral 2nd ACL injury in the first 2 years after RTS would be the same in groups that successfully met or failed to meet all RTS criteria prior to RTS. The second hypothesis was that quadriceps femoris strength at the time of RTS would identify which limb was at greatest risk for future ACL injury. Methods: One hundred eighty-one patients (116 female) with a mean age of 16.7±2.9 years old underwent ACLR and were released to return to pivoting/cutting sports. These patients were enrolled in a prospective, observational cohort study, completed a RTS assessment and were tracked for occurrence of an ipsilateral graft tear or contralateral ACL injury after ACLR for 24 months. The RTS assessment included 6 tests: isometric quadriceps strength, 4 functional hop tests and the International Knee Documentation Committee (IKDC) patient reported outcome survey. Limb symmetry index (LSI) was calculated for strength and hop test assessments [(inv/uninv)*100]. Subjects were classified into groups that successfully passed all 6 RTS tests at a level of 90 compared to those that failed to meet all 6 criteria. Chi Square tests and Fisher Exact Tests were used to determine if successfully passing all 6 RTS measures resulted in a reduced risk of 2nd ACL injury in the first 24 months after RTS as well as to assess if ability to successfully pass individual RTS criteria resulted in reduced risk of 2nd ACL injury. Results: Thirty-nine (21.5%) patients suffered a 2nd ACL injury with 18 ipsilateral graft failures and 21 contralateral ACL tears in the first 24 months after RTS following ACLR. At the time of RTS, 57 patients (31.5%) achieved LSI values of 90% or greater on all testing as well as an IDKC value of 90 or greater. At this level, there was no difference in ipsilateral graft failures between patients who passed all RTS criteria (15.8%) and those who failed at least 1 criterion (7.3%; p=0.08). There was also no difference in contralateral ACL injuries between patients who passed all RTS criteria (7.0%) and those who failed at least 1 criterion (13.7%; p=0.22). When individual RTS criterion were evaluated, patients who failed to achieve 90% quadriceps strength LSI were 84% less likely to suffer an ipsilateral graft failure (OR=0.16; 95%CI: 0.04, 0.74;p=0.009), but 3 times more likely to suffer a contralateral ACL injury (OR=2.5; 95%CI:1.0, 6.5;p=0.05). Conclusion: Current criteria to evaluate readiness to return young athletes to pivoting and cutting sports, may not identify young, active patients independently at high risk for a future ipsilateral graft tear or contralateral ACL injury. Inability to achieve 90% LSI on an isometric quadriceps strength assessment resulted in a reduced risk of ipsilateral graft failure, but an increased risk in contralateral ACL injury after ACLR and RTS. Further investigation is needed on the relationship between quad strength and side of future ACL injury and whether other factors may help contribute to a predictive model of future ACL injury specific to limb.

Background In the phase 3 MARIANNE trial, trastuzumab emtansine (T‐DM1) with or without pertuzumab showed noninferior progression‐free survival and better tolerability than trastuzumab plus a taxane (HT) for the first‐line treatment of human epidermal growth factor receptor 2 (HER2)–positive advanced breast cancer. This article reports the final descriptive overall survival (OS) analysis, updated safety data, and additional patient‐reported outcomes and biomarker analyses. Methods OS was assessed in 1095 patients with HER2‐positive breast cancer and no prior therapy for advanced disease who had been randomized to HT, T‐DM1 plus a placebo (hereafter T‐DM1), or T‐DM1 plus pertuzumab (T‐DM1+pertuzumab). A post hoc exploratory landmark analysis of OS, baseline patient and disease characteristics, and tumor biomarkers in patients with and without an objective tumor response (OR) according to the Response Evaluation Criteria in Solid Tumors within 6.5 months of randomization was conducted. Results The median OS was similar across groups (50.9, 53.7, and 51.8 months for the HT, T‐DM1, and T‐DM1+pertuzumab groups, respectively). Among patients with an OR, the median OS was longer with T‐DM1 (64.4 months) and T‐DM1+pertuzumab (not reached) versus HT (56.3 months). No baseline characteristics or biomarkers were strongly associated with OR. The incidence of grade 3 or higher adverse events was greater with HT (55.8%) than T‐DM1 (47.1%) or T‐DM1+pertuzumab (48.6%). The median time to clinically meaningful deterioration (a 3‐point or greater change) in neurotoxicity symptoms was shorter with HT (2.1 months) and T‐DM1+pertuzumab (4.2 months) than T‐DM1 (6.2 months). Fewer patients reported alopecia and diarrhea and were bothered by treatment side effects in the T‐DM1 arm. Conclusions These results support T‐DM1 as a first‐line treatment for patients with HER2‐positive metastatic breast cancer who are deemed unsuitable for taxane‐based therapy.

Twitter use has increased among patients with cancer, advocates, and oncology professionals. Hashtags, a form of metadata, can be used to share content, organize health information, and create virtual communities of interest. Cancer-specific hashtags modeled on a breast cancer community, #bcsm, led to the development of a structured set of hashtags called the cancer tag ontology. In this article, we review how these hashtags have worked with the aim of describing our experience from 2011 to 2017. We discuss useful guidelines for the development and maintenance of health-oriented communities on Twitter, including possible challenges to community sustainability and opportunities for future improvement and research.

Objectives: Data are lacking regarding implementation of novel strategies such as follow-up clinics and peer support groups, to reduce the burden of postintensive care syndrome. We sought to discover enablers that helped hospital-based clinicians establish post-ICU clinics and peer support programs, and identify barriers that challenged them. Design: Qualitative inquiry. The Consolidated Framework for Implementation Research was used to organize and analyze data. Setting: Two learning collaboratives (ICU follow-up clinics and peer support groups), representing 21 sites, across three continents. Subjects: Clinicians from 21 sites. Measurement and Main Results: Ten enablers and nine barriers to implementation of “ICU follow-up clinics” were described. A key enabler to generate support for clinics was providing insight into the human experience of survivorship, to obtain interest from hospital administrators. Significant barriers included patient and family lack of access to clinics and clinic funding. Nine enablers and five barriers to the implementation of “peer support groups” were identified. Key enablers included developing infrastructure to support successful operationalization of this complex intervention, flexibility about when peer support should be offered, belonging to the international learning collaborative. Significant barriers related to limited attendance by patients and families due to challenges in creating awareness, and uncertainty about who might be appropriate to attend and target in advertising. Conclusions: Several enablers and barriers to implementing ICU follow-up clinics and peer support groups should be taken into account and leveraged to improve ICU recovery. Among the most important enablers are motivated clinician leaders who persist to find a path forward despite obstacles.