Fluorescence lifetime imaging microscopy reveals sodium pump dimers in live cells.

The sodium-potassium ATPase (Na/K-ATPase, NKA) establishes ion gradients that facilitate many physiological functions including action potentials and secondary transport processes. NKA comprises a catalytic subunit (alpha) that interacts closely with an essential subunit (beta) and regulatory transmembrane micropeptides called FXYD proteins. In the heart, a key modulatory partner is the FXYD protein phospholemman (PLM, FXYD1), but the stoichiometry of the alpha-beta-PLM regulatory complex is unknown. Here, we used fluorescence lifetime imaging and spectroscopy to investigate the structure, stoichiometry, and affinity of the NKA-regulatory complex. We observed a concentration-dependent binding of the subunits of NKA-PLM regulatory complex, with avid association of the alpha subunit with the essential beta subunit as well as lower affinity alpha-alpha and alpha-PLM interactions. These data provide the first evidence that, in intact live cells, the regulatory complex is composed of two alpha subunits associated with two beta subunits, decorated with two PLM regulatory subunits. Docking and molecular dynamics (MD) simulations generated a structural model of the complex that is consistent with our experimental observations. We propose that alpha-alpha subunit interactions support conformational coupling of the catalytic subunits, which may enhance NKA turnover rate. These observations provide insight into the pathophysiology of heart failure, wherein low NKA expression may be insufficient to support formation of the complete regulatory complex with the stoichiometry (alpha-beta-PLM)2.

Evaluation of a Theory-Based Virtual Counseling Application in Nursing Education.

Effective communication skills in nursing are necessary for high-quality nursing care, but given the decline in nursing students' attitudes and their low self-confidence in effective communication with patients, a participatory and experiential training method is needed. Therefore, a virtual counseling application was developed using artificial intelligence and a three-dimensional avatar to facilitate learning of communication skills. This study aimed to evaluate the effectiveness of this theory-based virtual intervention on nursing students' learning attitudes, communication self-efficacy, and clinical performance. A longitudinal quasi-experimental study was conducted. Ninety-three undergraduate nursing students received virtual patient trainings with four clinical scenarios over 2 years. Data were analyzed using McNemar test and analysis of variance. Virtual patient training improved students' learning attitudes toward communication skills for scenarios involving the pregnant woman (20.4%, P = .03) and depressed patient (17.1%, P = .01) and enhanced perceived self-efficacy for scenarios involving the pregnant woman (22.6%, P = .002) and stressed nursing student (18.3%, P = .002). Students received lower clinical communication scores for pediatric, obstetric, and medical practicums compared with a previous cohort who received no training. Overall, this virtual counseling application can provide a valuable and cost-effective communication learning resource for the nursing curriculum.

Death and dying during COVID-19: The role of health care workers.

A correspondence to an article published in this journal showed that anticipatory grieving and loss during the Corona Virus Disease-19 (COVID-19) pandemic ultimately affects the lives of the family of the bereaved. Advocacy of the health care workers to the patient and their loved ones is necessary. This is where the role of health care workers appears to be important as they, in a sense, serve as a bridge to the dying patient and the grieving family.

The role of religiosity in COVID-19 vaccine hesitancy.

With the surge of COVID-19 cases worldwide, it is essential that vaccination be prioritized to facilitate herd immunity. However, there is vaccine hesitancy reflected in religiosity. This correspondence aims to understand religiosity as a factor that plays a role in vaccination hesitancy. Medical and scientifically sound evidence is influenced by religious beliefs resulting in varied responses toward getting vaccinated such as vaccination hesitancy.

Anticipatory grieving and loss during the COVID-19 pandemic.

Recent correspondence shows that death and burial practices deem significant in understanding the meaning and acceptance of the untimely and unexpected death of a family member afflicted with the coronavirus (COVID-19) disease. These, in turn, raise the need to address the anticipatory grieving process of the family. This paper examines the importance of anticipatory grieving that ultimately affects the lives of the family of the bereaved.

The truth must prevail: citizens' rights to know the truth during the era of COVID-19.

In a recent short report, the necessity of sophisticated practices in gathering records that would facilitate data sharing yields data-driven analysis in time of COVID-19. Consequently, there is a need to present the truth in data analytics in the era of COVID-19. This paper discusses the urgent call for people handling the COVID-19 data to be ethically responsible in their handling, processing, and reporting that impacts the lives of ordinary people especially in this time of pandemic as public health crisis.

TNFα selectively activates the IRE1α/XBP1 endoplasmic reticulum stress pathway in human airway smooth muscle cells.

Airway inflammation is a key aspect of diseases such as asthma. Proinflammatory cytokines such as TNFα mediate the inflammatory response. In various diseases, inflammation leads to endoplasmic reticulum (ER) stress, the accumulation of unfolded proteins, which triggers homeostatic responses to restore normal cellular function. We hypothesized that TNFα triggers ER stress through an increase in reactive oxygen species generation in human airway smooth muscle (hASM) with a downstream effect on mitofusin 2 (Mfn2). In hASM cells isolated from lung specimens incidental to patient surgery, dose- and time-dependent effects of TNFα exposure were assessed. Exposure of hASM to tunicamycin was used as a positive control. Tempol (500 µM) was used as superoxide scavenger. Activation of three ER stress pathways were evaluated by Western blotting: 1) autophosphorylation of inositol-requiring enzyme1 (IRE1α) leading to splicing of X-box binding protein 1 (XBP1); 2) autophosphorylation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) leading to phosphorylation of eukaryotic initiation factor 2α; and 3) translocation and cleavage of activating transcription factor 6 (ATF6). We found that exposure of hASM cells to tunicamycin activated all three ER stress pathways. In contrast, TNFα selectively activated the IRE1α/XBP1 pathway in a dose- and time-dependent fashion. Our results indicate that TNFα does not activate the PERK and ATF6 pathways. Exposure of hASM cells to TNFα also decreased Mfn2 protein expression. Concurrent exposure to TNFα and tempol reversed the effect of TNFα on IRE1α phosphorylation and Mfn2 protein expression. Selective activation of the IRE1α/XBP1 pathway in hASM cells after exposure to TNFα may reflect a unique homeostatic role of this pathway in the inflammatory response of hASM cells.

Increased mortality risk associated with serum sodium variations and borderline hypo- and hypernatremia in hospitalized adults.

BACKGROUND: This study aimed to evaluate short-term and long-term mortalities in a cohort of unselected hospitalized patients with serum sodium concentration ([Na+]) variations within and outside of reference range. METHODS: All adult patients admitted to the Mayo Clinic, Rochester, MN, USA from January 2011 to December 2013 (n = 147358) were retrospectively screened. Unique patients admitted during the study period were examined. The main exposure was serum [Na+] variation. Outcome measures were hospital and 1-year all-cause mortalities. RESULTS: A total of 60944 patients, mean age 63 ± 17 years, were studied. On admission, 17% (n = 10066) and 1.4% (n = 852) had hypo- and hypernatremia, respectively. During the hospital stay, 11044 and 4128 developed hypo- and hypernatremia, respectively, accounting for 52.3 and 82.9% of the total hypo- and hypernatremic patients. Serum [Na+] variations of ≥6 mEq/L occurred in 40.6% (n = 24 740) of the 60 944 patients and were significantly associated with hospital and 1-year mortalities after adjusting potential confounders (including demographics, comorbidities, estimated glomerular filtration rate, admission serum [Na+], number of [Na+] measurements and length of hospital stay). Adjusted odds ratios for hospital and 1-year mortalities increased with increasing [Na+] variations in a dose-dependent manner, from 1.47 to 5.48 (all 95% confidence intervals >1.0). Moreover, in fully adjusted models, [Na+] variations (≥6 mEq/L) within the reference range (135-145 mEq/L) or borderline hypo- or hypernatremia (133-137 and 143-147 mEq/L, respectively) compared with 138-142 mEq/L were associated with increased hospital and 1-year mortalities. CONCLUSION: In hospitalized adults, [Na+] fluctuation (≥6 mEq/L) irrespective of admission [Na+] and borderline hypo- or hypernatremia are independent predictors of progressively increasing short- and long-term mortality burdens.

Metadata Correction: A Virtual Counseling Application Using Artificial Intelligence for Communication Skills Training in Nursing Education: Development Study.

[This corrects the article DOI: 10.2196/14658.].

A Virtual Counseling Application Using Artificial Intelligence for Communication Skills Training in Nursing Education: Development Study.

BACKGROUND: The ability of nursing undergraduates to communicate effectively with health care providers, patients, and their family members is crucial to their nursing professions as these can affect patient outcomes. However, the traditional use of didactic lectures for communication skills training is ineffective, and the use of standardized patients is not time- or cost-effective. Given the abilities of virtual patients (VPs) to simulate interactive and authentic clinical scenarios in secured environments with unlimited training attempts, a virtual counseling application is an ideal platform for nursing students to hone their communication skills before their clinical postings. OBJECTIVE: The aim of this study was to develop and test the use of VPs to better prepare nursing undergraduates for communicating with real-life patients, their family members, and other health care professionals during their clinical postings. METHODS: The stages of the creation of VPs included preparation, design, and development, followed by a testing phase before the official implementation. An initial voice chatbot was trained using a natural language processing engine, Google Cloud's Dialogflow, and was later visualized into a three-dimensional (3D) avatar form using Unity 3D. RESULTS: The VPs included four case scenarios that were congruent with the nursing undergraduates' semesters' learning objectives: (1) assessing the pain experienced by a pregnant woman, (2) taking the history of a depressed patient, (3) escalating a bleeding episode of a postoperative patient to a physician, and (4) showing empathy to a stressed-out fellow final-year nursing student. Challenges arose in terms of content development, technological limitations, and expectations management, which can be resolved by contingency planning, open communication, constant program updates, refinement, and training. CONCLUSIONS: The creation of VPs to assist in nursing students' communication skills training may provide authentic learning environments that enhance students' perceived self-efficacy and confidence in effective communication skills. However, given the infancy stage of this project, further refinement and constant enhancements are needed to train the VPs to simulate real-life conversations before the official implementation.

Finding the Right Blend of Technologically Enhanced Learning Environments: Randomized Controlled Study of the Effect of Instructional Sequences on Interprofessional Learning.

BACKGROUND: With the availability and capabilities of varied technologically enhanced learning activities, the blended learning approach has become increasingly popular in interprofessional education. The combined use of different technologically enhanced learning activities has not been fully examined, particularly to determine the effects of instructional sequences for effective learning outcomes. OBJECTIVE: The objective of this study was to investigate whether the instructional sequences of a blended learning approach can improve students' learning outcomes on interprofessional competencies. METHODS: A randomized controlled study was conducted with 40 interprofessional health care teams. These teams undertook three technologically enhanced learning activities-Web-based instruction (WI), virtual reality (VR), and simulation exercise (SE)-after random assignment to three groups based on three different instructional sequences (WI-VR-SE, WI-SE-VR, and SE-WI-VR). Pretests and posttests were conducted to evaluate the students' learning outcomes on interprofessional competencies. RESULTS: A total of 198 participants from the three groups completed the questionnaires. All three groups reported significant improvement in their levels of self-efficacy (P<.05) and attitudes (P<.001) toward interprofessional team care about 1 month after the interprofessional learning activity. Although no significant difference was found (P=.06) between the WI-VR-SE and WI-SE-VR groups in the self-efficacy posttests, participants in the SE-WI-VR group reported significantly lower (P<.05) posttest scores than those in the WI-SE-VR group. The majority of the participants (137/198, 69.1%) selected the instructional sequence "WI-VR-SE" as their top preference. CONCLUSIONS: This study shows that the instructional sequence of a blended learning approach can have a significant impact on students' learning outcomes. The learning of concepts from WI followed by problem-solving activity in the SE was found to be a more effective learning sequence than the reverse sequence. We recommend that future studies focus on scaffolding students' learning when planning instructional sequences for technologically enhanced learning activities within blended learning environments.

Antihypertensive drug associated angioedema: effect modification by race/ethnicity.

PURPOSE: Assess angioedema risk with exposure to angiotensin converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) compared with beta-blockers, by race/ethnicity. METHODS: New-user cohorts of Medicare beneficiaries 65 years or older initiating ACEI, ARB, or beta-blocker treatment from March 2007 to March 2014 were constructed. Angioedema incidence rates by drug and race/ethnicity were computed for 1-30 and 31-365 days of treatment. Cox proportional hazards regression was used to examine angioedema risk between cohorts. RESULTS: Angioedema incidence rates (per 1000 person years) in beta-blocker users were 1.80 (whites), 4.11 (blacks), 1.89 (Asians), and 2.10 (Hispanics); in ACEI users, 4.03, 23.77, 2.94, and 4.27; and in ARB users, 1.73, 3.11, 1.10, and 1.90, respectively. Incidence rates were significantly higher in the first 30 days of exposure for all drug × race/ethnic groups. Overall, angioedema risk increased among ACEI users (hazard ratio, 2.91; 95% confidence interval, 2.75-3.07) but not ARB users (0.93, 0.85-1.02) versus beta-blocker users. Angioedema risk with ACEIs versus beta-blockers increased more in blacks (6.28, 5.44-7.24) than whites (2.33, 2.19-2.48), Hispanics (2.04, 1.36-3.07), and Asians (1.48, 0.94-2.35). Compared with white beta-blocker users, angioedema risk was increased 2.9-fold in whites, 20.2-fold in blacks, and 2.3-fold in other race/ethnic groups combined during the first 30 days of ACEI exposure. CONCLUSIONS: There was significant effect modification of angioedema risk by race and ACEI use for blacks, but not for other race/ethnicity groups. Angioedema risk was significantly greater in the first 30 days of exposure for all, and highest among blacks.

Balloon-Expandable Transcatheter Aortic Valves Can Be Successfully and Safely Implanted Transfemorally Without Balloon Valvuloplasty.

OBJECTIVES: To assess the necessity for balloon aortic valvuloplasty (BAV) during transfemoral transcatheter aortic valve implantation (TAVI) when using balloon-expandable valves. BACKGROUND: BAV is a usual part of TAVI procedures, prior to valve implantation. However, the benefits and necessity of this are unknown and recent evidence in self-expanding valves suggests it may not be necessary. METHODS: Retrospective single-center study of 154 patients undergoing first-time, transfemoral TAVI for native aortic valve stenosis, with (N = 76), and without (N = 78), BAV as part of the procedure. Data collected included demographic, procedural, and outcome data. RESULTS: BAV did not alter VARC-2 defined procedural success or early safety compared to not performing a BAV, including mortality, degree of aortic regurgitation, or need for post-TAVI balloon dilatation, although there was a strong trend to reduced stroke when not performing a BAV. There was a significantly reduced procedural time (P = 0.01) and fluoroscopic time (P < 0.001) without performing a BAV. There were no differences in cerebral embolization (solid, gaseous, or total emboli) noted between the 2 groups, as measured on transcranial doppler (TCD). CONCLUSIONS: TAVI can be effectively and safely performed without a BAV and this results in reduced procedural and fluoroscopic times, although embolization to the brain is not reduced. There is a trend toward reduced stroke risk. (J Interven Cardiol 2016;29:319-324).

Trimethoprim-sulfonamide use during the first trimester of pregnancy and the risk of congenital anomalies.

BACKGROUND: Sulfonamide antibacterials are widely used in pregnancy, but evidence about their safety is mixed. The objective of this study was to assess the association between first-trimester sulfonamide exposure and risk of specific congenital malformations. METHODS: Mother-infant pairs were selected from a cohort of 1.2 million live-born deliveries (2001-2008) at 11 US health plans comprising the Medication Exposure in Pregnancy Risk Evaluation Program. Mothers with first-trimester trimethoprim-sulfonamide (TMP-SUL) exposures were randomly matched 1:1 to (i) a primary comparison group (mothers exposed to penicillins and/or cephalosporins) and (ii) a secondary comparison group (mothers with no dispensing of an antibacterial, antiprotozoal, or antimalarial medication during the same time period). The outcomes were cardiovascular abnormalities, cleft palate/lip, clubfoot, and urinary tract abnormalities. RESULTS: We first identified 7615 infants in the TMP-SUL exposure group, of which 7595 (99%) were exposed to a combination of TMP-SUL and the remaining 1% to sulfonamides alone. After matching (1:1) to the comparator groups and only including those with complete data on covariates, there were 20 064 (n = 6688 per group) in the primary analyses. Overall, cardiovascular defects (1.52%) were the most common and cleft lip/palate (0.10%) the least common that were evaluated. Compared with penicillin/cephalosporin exposure, and no antibacterial exposure, TMP-SUL exposure was not associated with statistically significant elevated risks for cardiovascular, cleft lip/palate, clubfoot, or urinary system defects. CONCLUSIONS: First-trimester TMP-SUL exposure was not associated with a higher risk of the congenital anomalies studied, compared with exposure to penicillins and/or cephalosporins, or no exposure to antibacterials.

Acute Kidney Injury: Tubular Markers and Risk for Chronic Kidney Disease and End-Stage Kidney Failure.

Acute kidney injury (AKI) is a common clinical syndrome directly related to patient short-term and long-term morbidity and mortality. Over the last decade, the occurrence rate of AKI has been increasing, and there has also been a growing epidemic of chronic kidney diseases (CKD) and end-stage kidney disease (ESRD) linked to severe and repeated episodes of AKIs. The detection and management of AKI are currently far from satisfactory. A large proportion of AKI patients, especially those with preexisting CKD, are at an increased risk of non-resolving AKI and progressing to CKD and ESRD. Proposed pathological processes that contribute to the transition of AKI to CKD and ESRD include severity and frequency of kidney injury, alterations of tubular cell phenotype with cells predominantly in the G2/M phase, interstitial fibrosis and microvascular rarification related to loss of endothelial-pericyte interactions and pericyte dedifferentiation. Innate immune responses, especially dendritic cell responses related to inadequate adenosine receptor (2a)-mediated signals, autophagic insufficiency and renin-angiotensin system activation have also been implicated in the progression of AKI and transitions from AKI to CKD and ESRD. Although promising advances have been made in understanding the pathophysiology of AKI and AKI consequences, much more work needs to be done in developing biomarkers for detecting early kidney injury, prognosticating kidney disease progression and developing strategies to effectively treat AKI and to minimize AKI progression to CKD and ESRD.